pathway_id pathway_name entitya typea ida databasea entityb typeb idb databaseb effect mechanism residue sequence tax_id cell_data tissue_data modulator_complex target_complex modificationa modaseq modificationb modbseq pmid direct notes annotator sentence signor_id SIGNOR-EcmSynthesis ECM: ECM synthesis SLRP proteinfamily SIGNOR-PF31 SIGNOR ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 YES Proteoglycans are ubiquitous in connective tissue, and muscle ECM is no exception. A number of PGsare present in muscle ECM, and many belong to the family of small leucine-rich proteoglycans (SLRPs). SIGNOR-255345 SIGNOR-EcmSynthesis ECM: ECM synthesis COL14A1 protein Q05707 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 YES Types XII and XIV collagen are fibril-associated collagens with interrupted triple helices (FACITs) localized primarily to perimysium.23 While they appear to link fibrillar collagen to other ECM components, their precise function is not known SIGNOR-254672 SIGNOR-EcmSynthesis ECM: ECM synthesis COL12A1 protein Q99715 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 YES Types XII and XIV collagen are fibril-associated collagens with interrupted triple helices (FACITs) localized primarily to perimysium.23 While they appear to link fibrillar collagen to other ECM components, their precise function is not known SIGNOR-254671 SIGNOR-EcmSynthesis ECM: ECM synthesis COL1A1 protein P02452 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 YES Collagen is the major structural protein in skeletal muscle ECM;...Several studies suggest that perimysial collagen is predominantly type I SIGNOR-254662 SIGNOR-EcmSynthesis ECM: ECM synthesis COL18A1 protein P39060 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 YES Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present. Types XV and XVIII collagen are classified as multiplexins, which are heparan sulfate proteoglycans (HSPGs). The multiplexins can bind growth factors and also aid in linking the basement membrane to other basement membrane glycoproteins and endomysium SIGNOR-254679 SIGNOR-EcmSynthesis ECM: ECM synthesis COL6A3 protein P12111 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 YES Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present. SIGNOR-254675 SIGNOR-EcmSynthesis ECM: ECM synthesis COL1A2 protein P08123 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 YES Collagen is the major structural protein in skeletal muscle ECM;...Several studies suggest that perimysial collagen is predominantly type I SIGNOR-254663 SIGNOR-EcmSynthesis ECM: ECM synthesis COL15A1 protein P39059 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 YES Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present. Types XV and XVIII collagen are classified as multiplexins, which are heparan sulfate proteoglycans (HSPGs). The multiplexins can bind growth factors and also aid in linking the basement membrane to other basement membrane glycoproteins and endomysium SIGNOR-254678 SIGNOR-EcmSynthesis ECM: ECM synthesis COL6A6 protein A6NMZ7 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 YES Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present. SIGNOR-254677 SIGNOR-EcmSynthesis ECM: ECM synthesis COL6A1 protein P12109 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 YES Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present. SIGNOR-254673 SIGNOR-EcmSynthesis ECM: ECM synthesis COL6A2 protein P12110 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 YES Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present. SIGNOR-254674 SIGNOR-EcmSynthesis ECM: ECM synthesis COL3A1 protein P02461 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 YES Collagen is the major structural protein in skeletal muscle ECM;... type III collagen appears to be more evenly distributed between endomysium and epimysium SIGNOR-254664 SIGNOR-EosCCL11 Eosinophil: CCL11 Inflammation phenotype SIGNOR-PH12 SIGNOR IL4 protein P05112 UNIPROT up-regulates 9606 BTO:0000399 11290754 NO apalma Our findings indicate that chemokines acting via CCR3-initiated signaling pathways can very rapidly mobilize preformed stores of IL-4 from within human eosinophils. The means of extracellular release was by noncytotoxic, vesicular transport SIGNOR-255494 SIGNOR-EosCCL11 Eosinophil: CCL11 p38 proteinfamily SIGNOR-PF16 SIGNOR Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 11591790 NO The p21 G protein Rho and its targets, Rho-associated coiled-coil forming protein kinases (p160ROCK/ROCK I/ROKβ and Rho kinase/ROCK II/ROKα), play a crucial role in actin cytoskeleton reorganization SIGNOR-254360 SIGNOR-EosCCL11 Eosinophil: CCL11 CCL11 protein P51671 UNIPROT CCR3 protein P51677 UNIPROT up-regulates binding 9606 24702154 YES Eotaxin (CCL11) is a specific ligand for CCR3 and serves as a potent chemoattractant for eosinophils SIGNOR-254356 SIGNOR-EosCCL11 Eosinophil: CCL11 CCL11 protein P51671 UNIPROT CCR3 protein P51677 UNIPROT up-regulates activity binding 9606 BTO:0000399 10706854 YES Eotaxin and other CC chemokines acting via CC chemokine receptor-3 (CCR3) are believed to play an integral role in the development of eosinophilic inflammation in asthma and allergic inflammatory diseases. SIGNOR-256091 SIGNOR-EosCCL11 Eosinophil: CCL11 CCR3 protein P51677 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 11591790 NO We and others have recently found that eotaxin activates extracellular signal-regulated kinase (ERK)-1/2 and p38 mitogen-activated protein (MAP) kinases in eosinophils, and that these kinases are indispensable for eosinophil chemotaxis and degranulation SIGNOR-254357 SIGNOR-EosCCL11 Eosinophil: CCL11 CCR3 protein P51677 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 BTO:0000399 10706854 YES Activation of ERK2 and p38 by eotaxin is mediated through CCR3. SIGNOR-256093 SIGNOR-EosCCL11 Eosinophil: CCL11 CCR3 protein P51677 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates 9606 11591790 NO We and others have recently found that eotaxin activates extracellular signal-regulated kinase (ERK)-1/2 and p38 mitogen-activated protein (MAP) kinases in eosinophils, and that these kinases are indispensable for eosinophil chemotaxis and degranulation SIGNOR-254358 SIGNOR-EosCCL11 Eosinophil: CCL11 CCR3 protein P51677 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9606 BTO:0000399 10706854 YES Activation of ERK2 and p38 by eotaxin is mediated through CCR3. SIGNOR-256092 SIGNOR-EosCCR1 Eosinophil: CCR1 CCL7 protein P80098 UNIPROT CCR1 protein P32246 UNIPROT up-regulates binding 9606 14991608 YES For example, 11 chemokines are reported to bind to CC chemokine receptor (CCR) 1, including macrophage inflammatory protein (MIP)‐1α , MIP‐1β, MIP‐1δ, regulated upon activation, normal T cell‐expressed and secreted (RANTES), monocyte chemotactic peptide (MCP)‐1, MCP‐2, MCP‐3, MCP‐4, leukotactin‐1 (Lkn‐1), myeloid progenitor inhibitory factor (MPIF)‐1, and hemofiltrate CC chemokine (HCC)‐1 SIGNOR-254368 SIGNOR-EosCCR1 Eosinophil: CCR1 CCL5 protein P13501 UNIPROT CCR1 protein P32246 UNIPROT up-regulates binding 9606 10734056 YES RANTES interacts with specific cell surface receptors, which are coupled to pertussis toxin-sensitive guanine nucleotide regulatory proteins (G protein) to activate effectors such as phospholipase C (PLC), ion channels, phospholipase D, and protein kinase C. In addition to the CCR1 receptor, RANTES activates several members of the CC subfamily of chemokine receptors including CCR3, CCR4, and CCR5 SIGNOR-254367 SIGNOR-EosCCR1 Eosinophil: CCR1 CCL5 protein P13501 UNIPROT CCR3 protein P51677 UNIPROT up-regulates binding 9606 10734056 YES In addition to the CCR1 receptor, RANTES activates several members of the CC subfamily of chemokine receptors including CCR3, CCR4, and CCR5 SIGNOR-254370 SIGNOR-EosCCR1 Eosinophil: CCR1 CCR1 protein P32246 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 25230753 NO CCL3, an eosinophil precursor-produced chemokine that signals through CCR1, promotes terminal differentiation of CCR1-positive eosinophil precursors in the absence of IL-5, highlighting an autocrine loop capable of sustaining eosinophil differentiation SIGNOR-254369 SIGNOR-EosCCR1 Eosinophil: CCR1 CCL3 protein P10147 UNIPROT CCR1 protein P32246 UNIPROT up-regulates binding 9606 10734056 YES CCR1 is also activated by MIP-1α, MCP-2, and MCP-3, although maximum responses are only obtained with RANTES and MIP-1α. SIGNOR-254366 SIGNOR-EosIL5 Eosinophil: IL5 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 19819937 NO In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils. SIGNOR-254354 SIGNOR-EosIL5 Eosinophil: IL5 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 19819937 NO In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils. SIGNOR-254355 SIGNOR-EosIL5 Eosinophil: IL5 AKT proteinfamily SIGNOR-PF24 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 16982699 NO Protein kinase B (PKB/Akt) is an important modulator of insulin signaling, cell proliferation, and survival. Using small interfering RNA duplexes in nontransformed mammalian cells, we show that only Akt1 is essential for cell proliferation SIGNOR-254353 SIGNOR-EosIL5 Eosinophil: IL5 IL5 protein P05113 UNIPROT IL5RA protein Q01344 UNIPROT up-regulates binding -1 8567620 YES fspada Single chain and wt il5 also had similar binding affinity for soluble il5 receptor alpha chain, the specificity subunit of the il5 receptor, as measured kinetically with an optical biosensor. SIGNOR-40039 SIGNOR-EosIL5 Eosinophil: IL5 IL5 protein P05113 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 9606 21106848 NO It has been reported that IL-5 family members and selected chemotactic factors can activate the PI3K-Akt pathway in human blood eosinophils SIGNOR-254351 SIGNOR-EosIL5 Eosinophil: IL5 JAK2 protein O60674 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 4932 9575217 YES gcesareni Our mutational analysis suggests that the Stat5 SH2 domain is essential for the interaction with Jak2 and that the kinase domain of Jak2 is sufficient for Jak2-Stat5 interaction. Therefore, the Jak kinase domain may be all that is needed to cause Stat phosphorylation in situations where receptor docking is dispensable. [...] Most obviously, mutation of Tyr694 (Stat5a) or Tyr699 (Stat5b) to phenylalanine abolishes phosphorylation SIGNOR-56827 SIGNOR-EosIL5 Eosinophil: IL5 IL5RA protein Q01344 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation 9606 7602114 YES Jak 2 is physically associated with the IL-5b receptor. The binding of IL-5 to its receptor results in tyrosine phosphorylation and activation of Jak 2 tyrosine kinase within 1 to 3 min. SIGNOR-254352 SIGNOR-EosIL5 Eosinophil: IL5 IL5RA protein Q01344 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 21106848 NO Human blood eosinophils exhibit a hyperactive phenotype in response to chemotactic factors after cell priming with IL-5 family cytokines. Earlier work has identified ERK1/2 as molecular markers for IL-5 priming SIGNOR-254350 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis PI3K complex SIGNOR-C156 SIGNOR PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 12040186 YES lperfetto The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. SIGNOR-252713 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis PI3K complex SIGNOR-C156 SIGNOR PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates quantity 9606 21798082 YES lperfetto Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate. (pip2). SIGNOR-252722 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis PI3K complex SIGNOR-C156 SIGNOR PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 YES lperfetto Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478 SIGNOR-252712 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 BTO:0000150 19573809 NO lperfetto However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth SIGNOR-252703 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 12167717 NO lperfetto PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473, SIGNOR-252715 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis dexamethasone chemical CHEBI:41879 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 20956975 YES fspada Glucocorticoids, such as dexamethasone, have been used as in vitro inducers of adipogenesis. However, the roles of the glucocorticoid receptor (gr) in adipogenesis have not been well characterized yet. Here, we show that inhibition of gr activity using the gr antagonist ru486 prevents human mesenchymal stem cell and mouse embryonic fibroblast (mef) differentiation into adipocytes SIGNOR-168562 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKACA protein P17612 UNIPROT up-regulates chemical activation 9606 16293724 YES gcesareni Pge2 receptors are coupled to the G protein Gs, which causes accumulation of cyclic adenosine monophosphate (cAMP) and activates protein kinase a (PKA), we confirmed that PGE2 treatment or transfection of cells with the active catalytic subunit of PKA also stimulated the activity of a cAMP-responsive-element driven reporter gene (CRE-luc). SIGNOR-141786 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKACA protein P17612 UNIPROT up-regulates chemical activation 9606 BTO:0000007 22863277 YES milica The cAMP signaling cascade can activate protein kinase a (PKA) SIGNOR-198492 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis rosiglitazone chemical CHEBI:50122 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation 9534 7768881 YES An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma) SIGNOR-251646 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR GATA2 protein P23769 UNIPROT down-regulates activity phosphorylation Ser401 QTRNRKMsNKSKKSK 9606 BTO:0000876 15837948 YES PI-3K/Akt-dependent manner. lperfetto We show that insulin induces gata2 phosphorylation on serine 401 in a pi-3k/akt-dependent manner. Insulin-dependent phosphorylation of serine 401 impairs gata2 translocation to the nucleus and its dna binding activity SIGNOR-244271 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXA2 protein Q9Y261 UNIPROT down-regulates activity phosphorylation Thr156 KTYRRSYtHAKPPYS 9606 14500912 YES Foxa-2 physically interacts with Akt, a key mediator of the phosphatidylinositol 3-kinase pathway and is phosphorylated at a single conserved site (T156) that is absent in Foxa-1 and Foxa-3 proteins. This Akt phosphorylation site in Foxa-2 is highly conserved from mammals to insects. Mutant Foxa-2T156A is resistant to Akt-mediated phosphorylation, nuclear exclusion, and transcriptional inactivation of Foxa-2-regulated gene expression. SIGNOR-254974 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 21798082 YES lperfetto Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b). SIGNOR-252352 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 10090 BTO:0002572 18423396 YES lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation SIGNOR-252350 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates relocalization 10090 BTO:0002572 18423396 YES lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation SIGNOR-252351 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 YES lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. These results indicate that phosphorylation by PKB/Akt negatively regulates FKHR1 by promoting export from the nucleus. SIGNOR-252346 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 YES lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-252347 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 21440011 YES lperfetto Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs SIGNOR-252348 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser319 TFRPRTSsNASTISG 9606 11237865 YES lperfetto The transcription factor, forkhead in rhabdomyosarcoma (fkhr), is phosphorylated at three amino acid residues (thr-24, ser-256 and ser-319) by protein kinase b (pkb)alpha.Fkhr (forkhead in rhabdomyosarcoma), afx (all1 fused gene from chromosome x) and fkhrl1 (fkhr-like 1) are phosphorylated directly by pkb in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus SIGNOR-252349 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 ChEBI PDE1B protein Q01064 UNIPROT down-regulates activity chemical inhibition 9606 22014080 YES Until now, very few inhibitors of PDE1 were available for evaluating the contribution of PDE1 in tissue and cell function. Vinpocetine (Ahn et al., 1989) and 8-methoxymethyl-IBMX (Ahn et al., 1997) are common PDE1 inhibitors. SIGNOR-253400 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 ChEBI PDE1C protein Q14123 UNIPROT down-regulates activity chemical inhibition 9606 22014080 YES Until now, very few inhibitors of PDE1 were available for evaluating the contribution of PDE1 in tissue and cell function. Vinpocetine (Ahn et al., 1989) and 8-methoxymethyl-IBMX (Ahn et al., 1997) are common PDE1 inhibitors. SIGNOR-253017 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9534 9637919 YES lperfetto In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation. SIGNOR-58313 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 YES lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation -1 9094314 YES gcesareni We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1) SIGNOR-243274 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis PIP3 smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity relocalization 9606 BTO:0001130 23633519 YES lperfetto Akt is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates pips) with phosphate groups at positions 3,4 and 3,4,5 on the inositol ring. SIGNOR-236490 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis PIP3 smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity relocalization 9606 23119004 YES lperfetto Binding of IGF to IGF-1R activates PI3K to generate PIP3 which in turn recruits and activates proteins that contain a pleckstrin homology ph) domain, including AKT and PDK1. SIGNOR-236509 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis PDE1A protein P54750 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI down-regulates quantity chemical modification 9606 22014080 YES PDE1A and PDE1B preferentially hydrolyse cGMP, whereas PDE1C hydrolyses cAMP and cGMP with similar Km values SIGNOR-253398 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis PDE1C protein Q14123 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI down-regulates quantity chemical modification 9606 22014080 YES PDE1A and PDE1B preferentially hydrolyse cGMP, whereas PDE1C hydrolyses cAMP and cGMP with similar Km values SIGNOR-253399 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates activity phosphorylation Ser241 SKQARANsFVGTAQY 9606 11481331 YES miannu In terms of the modulation of PDK1 activity by reversible phosphorylation, five pS sites have been identified on PDK1 in vivo, but only one of these sites, Ser-241 in the activation loop of PDK1, is essential for activity. It seems likely that PDK1 autophosphorylates itself on this residue. SIGNOR-250268 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates activity phosphorylation Ser241 SKQARANsFVGTAQY 9606 10455013 YES lperfetto Pdk1 is itself phosphorylated in vivo and whether phosphorylation plays a role in regulating its activity/ phosphorylation of ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1 SIGNOR-236789 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT down-regulates quantity by destabilization phosphorylation Ser241 SKQARANsFVGTAQY -1 12177059 YES miannu PDK1 kinase activity is negatively regulated by binding to 14-3-3 through the PDK1 autophosphorylation site Ser-241. PDK1 binds to 14-3-3 in vivo and in vitro through the residues surrounding the autophosphorylation site Ser-241 and that the association is achieved only when Ser-241 has been phosphorylated SIGNOR-250077 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10090 12808134 YES lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1). SIGNOR-134477 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15743829 YES lperfetto 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt), SIGNOR-244469 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10116 BTO:0000142 10226025 YES lperfetto Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown. SIGNOR-244421 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 YES lperfetto The activation of PKBbeta and PKBamma by PDK11 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma) SIGNOR-244480 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr992 DGPLGPLyASSNPEY -1 3166375 YES lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-106522 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr999 YASSNPEyLSASDVF -1 3166375 YES lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-106526 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1355 SLGFKRSyEEHIPYT -1 3166375 YES lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-22577 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1361 SYEEHIPyTHMNGGK -1 3166375 YES lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-233560 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1011 DVFPCSVyVPDEWEV -1 3166375 YES lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-233564 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1185 FGMTRDIyETDYYRK -1 2449432 YES lperfetto We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151; SIGNOR-106510 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1189 RDIYETDyYRKGGKG -1 2449432 YES lperfetto We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151; SIGNOR-106514 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1190 DIYETDYyRKGGKGL -1 2449432 YES lperfetto We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151; SIGNOR-106518 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis INSR protein P06213 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation Tyr580 LRKTRDQyLMWLTQK 9534 BTO:0000298 8385099 YES The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor. SIGNOR-252691 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis INSR protein P06213 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation Tyr368 STKMHGDyTLTLRKG 9534 8385099 YES The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor. SIGNOR-252692 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis INSR protein P06213 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation Tyr607 NENTEDQySLVEDDE 9534 BTO:0000298 8385099 YES The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor. SIGNOR-252693 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis FOXO1 protein Q12778 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 16670091 NO lperfetto FOXO1 coexpression dose-dependently repressed transcription from either the PPARgamma 1 or PPARgamma2 promoter reporter by 65%, whereas insulin (100 nm, 20-24 h) either partially or completely reversed this effect. SIGNOR-218013 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis FOXO1 protein Q12778 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 18423396 NO fspada Akt1/Pkb-alpha was found to be the major regulator of phosphorylation and nuclear export of Foxo1, whose presence in the nucleus strongly attenuates adipocyte differentiation. SIGNOR-178281 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis FOXO1 protein Q12778 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 12530968 NO Constitutively active Foxo1 prevents the differentiation of preadipocytes, while dominant-negative Foxo1 restores adipocyte differentiation of fibroblasts from insulin receptor-deficient mice. SIGNOR-254973 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis INS protein P01308 UNIPROT INSR protein P06213 UNIPROT up-regulates activity binding 10029 16956584 YES lperfetto Insulin binds to the alpha subunit of the insulin receptor (IR) on the cell surface. SIGNOR-236748 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis INS protein P01308 UNIPROT INSR protein P06213 UNIPROT up-regulates activity binding 9606 2550426 YES lperfetto Our previous studies indicated that amino acid residues 240-250 in the cysteine-rich region of the human insulin receptor alpha-subunit constitute a site in which insulin binds. SIGNOR-23001 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis FOXA2 protein Q9Y261 UNIPROT DLK1 protein P80370 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 12865419 YES Taken together, these data suggest that Foxa-2 is a direct transcriptional activator of the Pref-1 gene. SIGNOR-254971 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis DLK1 protein P80370 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 8500166 NO This indicates that pref-1 functions as a negative regulator of adipocyte differentiation, possibly in a manner analogous to EGF-like proteins that govern cell fate decisions in invertebrates. SIGNOR-254980 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis CREB1 protein P16220 UNIPROT CEBPB protein P17676 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 14593102 NO lperfetto Expression of constitutively active CREB strongly activated C/EBPbeta promoter-reporter genes, induced expression of endogenous C/EBPbeta, and caused adipogenesis in the absence of the hormonal inducers normally required SIGNOR-250573 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis CREB1 protein P16220 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000759 14614508 NO HES-1 is a direct CREB target in vivo. SIGNOR-254742 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis HES1 protein Q14469 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates activity 9606 BTO:0001938 24300895 YES Altering the expression of HES1 did not obviously affect GR abundance (Figure 3A). However, genome-wide microarrays revealed that overexpression of HES1 resulted in inhibition of GR-mediated changes in the glucocorticoid regulated transcriptome, as compared to non-overexpressing controls SIGNOR-253064 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis HES1 protein Q14469 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 14614508 NO Overexpression of HES-1 fully repressed PPAR-g even in the presence of the ACREB inhibitor, showing that HES-1 acts downstream of CREB SIGNOR-254743 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis HES1 protein Q14469 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 BTO:0000011 16282371 NO Notch signaling blocks differentiation of 3T3-L1 preadipocytes, and this can be mimicked by constitutive expression of the Notch target gene Hes-1 SIGNOR-253058 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis PPARG protein P37231 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 16150867 NO lperfetto Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor SIGNOR-228622 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis PRKACA protein P17612 UNIPROT PPARG protein P37231 UNIPROT up-regulates activity 10090 BTO:0000011 20638365 NO Here we showed that cAMP-induced activation of protein kinase A (PKA) and Akt is essential for the transcriptional activation of PPAR-gamma SIGNOR-253019 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001103 21902831 YES gcesareni Phosphorylation of CREB by PKA allows it to initiate the transcription of genes that contain a CRE element, two of which are PAX3 and MYF5. SIGNOR-176560 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000669 15568017 YES gcesareni Using a combination of in vitro explant assays, mutant analysis and gene delivery into mouse embryos cultured ex vivo, we demonstrate that adenylyl cyclase signalling via PKA and its target transcription factor CREB are required for WNT-directed myogenic gene expression. SIGNOR-131307 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis GATA2 protein P23769 UNIPROT PPARG protein P37231 UNIPROT down-regulates activity 9606 20510530 YES fferrentino GATA2 interacts directly with PPARG and C/EBP a , which may deplete PPARG involved in the promotion of adipogenesis SIGNOR-132949 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis GATA2 protein P23769 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 11021798 NO fspada Constitutive gata-2 and gata-3 expression suppressed adipocyte differentiation and trapped cells at the preadipocyte stage. SIGNOR-78659 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis CEBPB protein P17676 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity transcriptional regulation 10090 16431920 YES fspada These data suggest that c/CEBP beta activates a single unified pathway of adipogenesis involving its stimulation of PPARgamma expression, which then activates C/EBP alpha expression by dislodging HDAC1 from the promoter for degradation in the proteasome SIGNOR-143952 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis CEBPB protein P17676 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 11884404 NO fferrentino Overexpression and ribozyme-mediated targeting of transcriptional coactivators CREB-binding protein and p300 revealed their indispensable roles in adipocyte differentiation through the regulation of peroxisome proliferator-activated receptor gamma. SIGNOR-250564 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis CEBPB protein P17676 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0000011 25451943 NO gcesareni Adipogenesis is controlled by a transcriptional cascade composed of a large number of transcriptional factors, among which CCAAT/enhancer-binding protein (C/EBP) β plays an essential role. SIGNOR-238297 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis ADCY1 protein Q08828 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates chemical modification 9606 22863277 YES milica To further explore the role of camp signaling in the hippo pathway, we treated cells with forskolin, an activator of adenylyl cyclase that results in cAMP production. SIGNOR-198486 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis ADCY1 protein Q08828 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates chemical modification 9606 17251915 YES gcesareni Typically Gas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate many molecules, including phospholipases, ion channels and lipid kinases. SIGNOR-152546 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis NR3C1 protein P04150 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates binding 10116 18762022 YES The GR directly interferes with Hes1 promoter activity, triggering the recruitment of histone deacetylase (HDAC) activities to the Hes1 gene SIGNOR-253057 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis NR3C1 protein P04150 UNIPROT CEBPB protein P17676 UNIPROT up-regulates activity binding 10116 9428795 YES We have shown that one of the functions of the GR to activate transcription of the AGP gene is to recruit C/EBPbeta and to maintain it bound at its target DNA sequences (SRU) SIGNOR-251655 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis NR3C1 protein P04150 UNIPROT CEBPB protein P17676 UNIPROT up-regulates activity binding 10090 BTO:0000011 11279134 YES lperfetto The differentiation of 3T3-L1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor gamma (PPARgamma) by dexamethasone (DEX), 3-isobutyl-1-methylxanthine (MIX), and insulin SIGNOR-250566 SIGNOR-FAPadipo FAP: In vitro induction of adipogenesis HDAC1 protein Q13547 UNIPROT HES1 protein Q14469 UNIPROT down-regulates quantity transcriptional regulation 10090 18762022 NO These data suggest that the GR recruits cellular HDAC activities to the Hes1 promoter, thereby conferring transcriptional repression in response to GC signaling. SIGNOR-253054 SIGNOR-FapATC FAP: Adipogenic transcriptional cascade RXRA protein P19793 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 11237216 YES gcesareni Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology SIGNOR-105445 SIGNOR-FapATC FAP: Adipogenic transcriptional cascade FOXO1 protein Q12778 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 16670091 NO lperfetto FOXO1 coexpression dose-dependently repressed transcription from either the PPARgamma 1 or PPARgamma2 promoter reporter by 65%, whereas insulin (100 nm, 20-24 h) either partially or completely reversed this effect. SIGNOR-218013 SIGNOR-FapATC FAP: Adipogenic transcriptional cascade CREB1 protein P16220 UNIPROT CEBPB protein P17676 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 14593102 NO lperfetto Expression of constitutively active CREB strongly activated C/EBPbeta promoter-reporter genes, induced expression of endogenous C/EBPbeta, and caused adipogenesis in the absence of the hormonal inducers normally required SIGNOR-250573 SIGNOR-FapATC FAP: Adipogenic transcriptional cascade PPARG protein P37231 UNIPROT CEBPA protein P49715 UNIPROT up-regulates activity transcriptional regulation 10090 BTO:0002572;BTO:0000011;BTO:0005065 16431920 NO Dislodging hdac1 from the promoter lperfetto These data suggest that c/ebp beta activates a single unified pathway of adipogenesis involving its stimulation of ppargamma expression, which then activates c/ebp alpha expression by dislodging hdac1 from the promoter for degradation in the proteasome SIGNOR-235358 SIGNOR-FapATC FAP: Adipogenic transcriptional cascade PPARG protein P37231 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0004300 16150867 NO lperfetto Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor SIGNOR-256229 SIGNOR-FapATC FAP: Adipogenic transcriptional cascade GATA3 protein P23771 UNIPROT CEBPB protein P17676 UNIPROT down-regulates binding 10090 15632071 YES fspada In the present study, we demonstrate that both gata-2 and gata-3 form protein complexes with ccaat/enhancer binding protein alpha (c/ebpalpha) and c/ebpbeta, members of a family of transcription factors that are integral to adipogenesis. []the interaction between gata and c/ebp factors is critical for the ability of gata to suppress adipocyte differentiation. SIGNOR-132952 SIGNOR-FapATC FAP: Adipogenic transcriptional cascade GATA3 protein P23771 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 15632071 NO fspada Constitutive expression of both gata-2 and gata-3 suppressed adipocyte differentiation, partially through direct binding to the peroxisome proliferator-activated receptor gamma (ppargamma) promoter and suppression of its basal activity SIGNOR-132955 SIGNOR-FapATC FAP: Adipogenic transcriptional cascade GATA3 protein P23771 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 11021798 NO fspada Constitutive gata-2 and gata-3 expression suppressed adipocyte differentiation and trapped cells at the preadipocyte stage. SIGNOR-78830 SIGNOR-FapATC FAP: Adipogenic transcriptional cascade GATA2 protein P23769 UNIPROT PPARG protein P37231 UNIPROT down-regulates activity 9606 20510530 YES fferrentino GATA2 interacts directly with PPARG and C/EBP a , which may deplete PPARG involved in the promotion of adipogenesis SIGNOR-132949 SIGNOR-FapATC FAP: Adipogenic transcriptional cascade GATA2 protein P23769 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 11021798 NO fspada Constitutive gata-2 and gata-3 expression suppressed adipocyte differentiation and trapped cells at the preadipocyte stage. SIGNOR-78659 SIGNOR-FapATC FAP: Adipogenic transcriptional cascade RXRB protein P28702 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 11237216 YES lperfetto Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology SIGNOR-105454 SIGNOR-FapATC FAP: Adipogenic transcriptional cascade CEBPD protein P49716 UNIPROT KLF5 protein Q13887 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16054042 NO fspada Klf5 expression is induced by c/ebpbeta and delta. KLF5, in turn, acts in concert with c/ebpbeta/delta to activate the ppargamma2 promoter. SIGNOR-210007 SIGNOR-FapATC FAP: Adipogenic transcriptional cascade CEBPB protein P17676 UNIPROT KLF5 protein Q13887 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16054042 NO fspada Klf5 expression is induced by c/ebpbeta and delta. KLF5, in turn, acts in concert with c/ebpbeta/delta to activate the ppargamma2 promoter. SIGNOR-210004 SIGNOR-FapATC FAP: Adipogenic transcriptional cascade CEBPB protein P17676 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates quantity transcriptional regulation 10090 22355693 YES These results show that GSK3β is involved in regulating phosphorylation and activation of C/EBPβ and that this transcription factor is required to transactivate srebf1a expression, leading to the early steps of adipogenesis SIGNOR-251645 SIGNOR-FapATC FAP: Adipogenic transcriptional cascade CEBPB protein P17676 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity transcriptional regulation 10090 16431920 YES fspada These data suggest that c/CEBP beta activates a single unified pathway of adipogenesis involving its stimulation of PPARgamma expression, which then activates C/EBP alpha expression by dislodging HDAC1 from the promoter for degradation in the proteasome SIGNOR-143952 SIGNOR-FapATC FAP: Adipogenic transcriptional cascade SREBF1 protein P36956 UNIPROT PPARG protein P37231 UNIPROT up-regulates activity 10090 9539737 NO gcesareni Finally, we demonstrate directly that cells expressing ADD1/SREBP1 produce and secrete lipid molecule(s) that bind directly to PPARgamma, displacing the binding of radioactive thiazolidinedione ligands SIGNOR-170607 SIGNOR-FapATC FAP: Adipogenic transcriptional cascade CEBPA protein P49715 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 17139329 NO fferrentino C/EBPα induces many adipocyte genes directly, and in vivo studies indicate an important role for this factor in the development of adipose tissue. SIGNOR-132946 SIGNOR-FapATC FAP: Adipogenic transcriptional cascade KLF5 protein Q13887 UNIPROT PPARG protein P37231 UNIPROT up-regulates transcriptional regulation 10090 16054042 NO fspada Klf5 expression is induced by c/ebpbeta and delta. KLF5, in turn, acts in concert with c/ebpbeta/delta to activate the ppargamma2 promoter. SIGNOR-210010 SIGNOR-FapATC FAP: Adipogenic transcriptional cascade NR3C1 protein P04150 UNIPROT CEBPB protein P17676 UNIPROT up-regulates activity binding 10116 9428795 YES We have shown that one of the functions of the GR to activate transcription of the AGP gene is to recruit C/EBPbeta and to maintain it bound at its target DNA sequences (SRU) SIGNOR-251655 SIGNOR-FapATC FAP: Adipogenic transcriptional cascade NR3C1 protein P04150 UNIPROT CEBPB protein P17676 UNIPROT up-regulates activity binding 10090 BTO:0000011 11279134 YES lperfetto The differentiation of 3T3-L1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor gamma (PPARgamma) by dexamethasone (DEX), 3-isobutyl-1-methylxanthine (MIX), and insulin SIGNOR-250566 SIGNOR-FapATC FAP: Adipogenic transcriptional cascade NR3C1 protein P04150 UNIPROT CEBPD protein P49716 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0000011 1840554 YES The expression levels of both C/EBPB and C/EBPD are increased dramatically during the time of hormonal stimulation (see Fig. 8). Furthermore, the C/EBPB- and C/EBPD encoding genes are activated directly by adipogenic hormones SIGNOR-251648 SIGNOR-FapATC FAP: Adipogenic transcriptional cascade NR3C1 protein P04150 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0000011 8754811 NO ggiuliani Induction of peroxisome proliferator-activated receptor gamma during the conversion of 3T3 fibroblasts into adipocytes is mediated by C/EBPbeta, C/EBPdelta, and glucocorticoids. The dose of DEX required to promote maximal expression of PPARg mRNA is approximately 10 nM, which is within the range of the Kd for the association of DEX with the glucocorticoid receptor in 3T3-L1 cells. SIGNOR-255963 SIGNOR-FapBMP FAP: BMP SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR form complex binding 9606 20957627 YES lperfetto Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus. SIGNOR-255838 SIGNOR-FapBMP FAP: BMP SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR DLX5 protein P56178 UNIPROT up-regulates transcriptional regulation 10090 BTO:0000165 12815054 NO ggiuliani Over-expression of Smad1 or Smad5, mediators of BMP-signaling, also induced Dlx5 expression even in the absence of BMP-2 treatment concomitant with positive ALP staining SIGNOR-255837 SIGNOR-FapBMP FAP: BMP SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates activity binding 9606 BTO:0000567 15573378 YES ggiuliani The Runx2 WT and deletion constructs (1 √¢‚Ǩ‚Äú495, 1√¢‚Ǩ‚Äú464, and 1√¢‚Ǩ‚Äú432) all physically interact with the BMP2 responsive Smad 1 SIGNOR-255834 SIGNOR-FapBMP FAP: BMP SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates transcriptional regulation 10090 BTO:0000165 11073979 NO ggiuliani As shown in Fig. 8A, overexpression of Smad5 by itself induced Runx2 expression even in the absence of BMP-2 (lane 5). Western blot analysis also confirmed the induced level of Runx2 protein in C2C12-Sm5 cells (Fig. 8B) SIGNOR-255835 SIGNOR-FapBMP FAP: BMP SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates transcriptional regulation 9606 27563484 NO ggiuliani Smad1/5/8-Smad4 complex transcribed Runx2 expression, as they complex with Runx2 to initiate other osteoblast gene expression. SIGNOR-255836 SIGNOR-FapBMP FAP: BMP RUNX2 protein Q13950 UNIPROT SP7 protein Q8TDD2 UNIPROT up-regulates transcriptional regulation 10090 16574347 NO Giulio Giuliani Osx promoter activity was up-regulated by 2 fold after Runx2 over-expression in ATDC5 cells. Osx Is Phosphorylated by p38 at Ser-73 and Ser-77 SIGNOR-255410 SIGNOR-FapBMP FAP: BMP RUNX2 protein Q13950 UNIPROT Osteoblast_differentiation phenotype SIGNOR-PH9 SIGNOR up-regulates 10090 9182762 NO gcesareni Osf2/cbfa1 as an osteoblast-specific transcription factor and as a regulator of osteoblast differentiation SIGNOR-48940 SIGNOR-FapBMP FAP: BMP SP7 protein Q8TDD2 UNIPROT Osteoblast_differentiation phenotype SIGNOR-PH9 SIGNOR up-regulates 10090 11792318 NO Giulio Giuliani Our results established that the novel transcription factor Osx is required for osteoblast differentiation and hence for bone formation. SIGNOR-255449 SIGNOR-FapBMP FAP: BMP BMPR1A protein P36894 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 10090 10712517 YES gcesareni Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors SIGNOR-75652 SIGNOR-FapBMP FAP: BMP BMPR1A protein P36894 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity 10090 8533096 NO ggiuliani We also examined whether TAK1 was activated by bone morphogenetic protein (BMP). BMP-4 also stimulated TAK1 activity in a time- and dose-dependent manner SIGNOR-255815 SIGNOR-FapBMP FAP: BMP BMPR1A protein P36894 UNIPROT SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000165;BTO:0002974; BTO:0002809 9442019 YES ggiuliani In this study, we isolated human Smad5 and found that Smad5 was involved in BMP-2 signaling cascades, which mediate the bone-inducing effects of BMP-2. Smad5 was directly serine-phosphorylated by BMPIR through a physical interaction. The activated Smad5 subsequently formed a complex with DPC4, and this complex was then translocated to the nucleus. SIGNOR-255830 SIGNOR-FapBMP FAP: BMP BMPR1A protein P36894 UNIPROT SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR up-regulates activity phosphorylation 10090 BTO:0004058 19620713 YES ggiuliani The expression of CA-BMPr1A and CA-BMPr1B mRNA was confirmed by RT-PCR using appropriate primers to distinguish expression of the constitutively active receptors from endogenous BMP receptors; specific antibodies for these receptors were not available. However, the functional effects of their expression, i.e., phosphorylation of Smad1/5/8 and p38 MAPK, verify overexpression of the constitutively active receptors (Fig. 3B). Thus, their overexpression provoked a substantial rise in the phosphorylation of Smad1/5/8 and p38 MAPK, known downstream phosphorylated intermediates in the BMP signaling pathway (Fig. 3B) (16, 17). SIGNOR-255831 SIGNOR-FapBMP FAP: BMP DLX5 protein P56178 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22298955 NO gcesareni Dlx5 can drive runx2 expression and osteogenic differentiation in developing cranial suture mesenchyme , indicat-ing that dlx5 can work as an upstream gene of runx2. SIGNOR-195576 SIGNOR-FapBMP FAP: BMP DLX5 protein P56178 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17335796 NO gcesareni Dlx5 can drive runx2 expression and osteogenic differentiation in developing cranial suture mesenchyme. SIGNOR-153454 SIGNOR-FapBMP FAP: BMP DLX5 protein P56178 UNIPROT Osteoblast_differentiation phenotype SIGNOR-PH9 SIGNOR up-regulates 10090 12000792 NO Giulio Giuliani In conclusion, Dlx5 and Dlx6 are dynamic regulators of mammalian development, which are absolutely required for proper craniofacial and skeletal development and which display overlapping genetic functions in all tissues in which they are expressed. In addition, they appear to act as essential regulators of chondrogenesis and osteogenesis. SIGNOR-255450 SIGNOR-FapBMP FAP: BMP MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Thr180 RHTDDEMtGYVATRW 9606 8622669 YES lperfetto Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. SIGNOR-40349 SIGNOR-FapBMP FAP: BMP MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 8622669 YES lperfetto Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. SIGNOR-40353 SIGNOR-FapBMP FAP: BMP MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000130;BTO:0000801;BTO:0000876 7535770 YES lperfetto Recently, two map kinase kinases (mkk3 and mkk4) that activate p38 map kinase have been identified. the mechanism of p38 activation is mediated by dual phosphorylation on thr-180 and tyr-182. SIGNOR-236103 SIGNOR-FapBMP FAP: BMP MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 8622669 YES lperfetto Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. MKK3 is therefore a specific activator of p38 MAP kinase that is independent of the JNK and ERK signaling pathways. SIGNOR-40356 SIGNOR-FapBMP FAP: BMP MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9534 7839144 YES lperfetto Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. SIGNOR-232156 SIGNOR-FapBMP FAP: BMP MAP3K7 protein O43318 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 11460167 YES lperfetto The activity of tak1 to phosphorylate mkk6, which activates the jnk-p38 kinase pathway, is directly regulated by k63-linked polyubiquitination SIGNOR-109497 SIGNOR-FapBMP FAP: BMP MAP3K7 protein O43318 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 21902831 YES lperfetto Tak1 can phosphorylate and activate map kinase kinase 3/6 (mkk3/6), and numerous studies have demonstrated a requirement for mkk3/6 activity in the initiation of myoblast differentiation, again in a p38-dependent manner. SIGNOR-236145 SIGNOR-FapBMP FAP: BMP MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Ser192 HMTNNKGsAAWMAPE -1 20538596 YES lperfetto Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation. SIGNOR-232153 SIGNOR-FapBMP FAP: BMP MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Ser192 HMTNNKGsAAWMAPE 9606 10702308 YES lperfetto A mutant of TAK1 that lacks kinase activity is not phosphorylated either following IL-1 treatment or when coexpressed with TAB1, indicating that TAK1 phosphorylation is due to autophosphorylation. Furthermore, mutation to alanine of a conserved serine residue (Ser-192) in the activation loop between kinase domains VII and VIII abolishes both phosphorylation and activation of TAK1. These results suggest that IL-1 and ectopic expression of TAB1 both activate TAK1 via autophosphorylation of Ser-192. SIGNOR-235758 SIGNOR-FapBMP FAP: BMP MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Thr184 GTACDIQtHMTNNKG -1 20538596 YES lperfetto Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation. SIGNOR-227544 SIGNOR-FapBMP FAP: BMP MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Thr178 LKICDFGtACDIQTH -1 20538596 YES lperfetto Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation. SIGNOR-227536 SIGNOR-FapBMP FAP: BMP MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Thr187 CDIQTHMtNNKGSAA -1 20538596 YES lperfetto Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation. SIGNOR-227540 SIGNOR-FapBMP FAP: BMP MAP3K7 protein O43318 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000222 21902831 YES lperfetto TAK1 can phosphorylate and activate MAP kinase kinase 3/6 (MKK3/6), and numerous studies have demonstrated a requirement for MKK3/6 activity in the initiation of myoblast differentiation, again in a p38-dependent manner. SIGNOR-236093 SIGNOR-FapBMP FAP: BMP MAP3K7 protein O43318 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 10090 17299140 YES lperfetto Taken together, our data indicate that TAK1 and TAB1 play a pivotal role as upstream signal transducers activating the MKK3-p38 MAPK signaling cascade that leads to the induction of type I collagen expression by TGF-beta(1). In addition, our findings also suggest that TAK1 has a novel function in regulation of the steady-state protein levels of MKK3 and p38 MAPK. SIGNOR-42402 SIGNOR-FapBMP FAP: BMP BMP2 protein P12643 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates activity binding 9534 SIGNOR-C29 7791754 YES lperfetto Under our assay conditions, bmp-2 binds better to bmpr-ii in combination with actr-i or bmpr-ib than in combination with bmpr-ia SIGNOR-144101 SIGNOR-FapBMP FAP: BMP BMP2 protein P12643 UNIPROT BMP2 protein P12643 UNIPROT up-regulates binding 9606 BTO:0000887 11178121 YES lperfetto Bmps are dimeric proteins with a single interchain disulfide bond. The dimeric conformation is an absolute requirement for the biological action and interaction with receptors SIGNOR-236166 SIGNOR-FapBMP FAP: BMP BMP2 protein P12643 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates activity binding -1 18937504 YES ggiuliani Here we report the high-resolution NMR structure of BMPR-IA ECD in solution, revealing that a large part of the ligand-binding epitope is unfolded and flexible before formation of the complex. The binding beta4beta5 loop of BMPR-IA passes through a structural rearrangement upon BMP-2 binding. SIGNOR-255771 SIGNOR-FapBMP FAP: BMP BMPR2 protein Q13873 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates binding 9534 7791754 YES fspada Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor. SIGNOR-33440 SIGNOR-FapBMP FAP: BMP BMPR2 protein Q13873 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C29 SIGNOR-C29 18756288 YES gcesareni Bmp ligands bind to the bmp receptors bmpr1 and bmpr2, and bmpr2 then phosphorylates and activates bmpr1. SIGNOR-180545 SIGNOR-FapBMP FAP: BMP BMPR2 protein Q13873 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates activity binding 10090 10712517 YES ggiuliani Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known BMP type I receptors (BR-Ia and BR-Ib) and the BMP type II receptor (BR-II). Coimmunoprecipitation studies detected the formation of heteromeric and homomeric complexes among all the BMP receptor types even in the absence of ligand. SIGNOR-255781 SIGNOR-FapBMP FAP: BMP MAPK14 protein Q16539 UNIPROT DLX5 protein P56178 UNIPROT up-regulates activity phosphorylation Ser34 MHHPSQEsPTLPESS 10090 18056716 YES ggiuliani We show that Dlx5 is a novel substrate for p38 MAPK in vitro and in vivo and that Ser-34 and Ser-217 are the sites phosphorylated by p38 SIGNOR-255792 SIGNOR-FapBMP FAP: BMP MAPK14 protein Q16539 UNIPROT SP7 protein Q8TDD2 UNIPROT up-regulates activity phosphorylation 10090 20682789 YES ggiuliani We therefore propose that Osterix binds to Sp1 sequences on target gene promoters and that its phosphorylation by p38 enhances recruitment of coactivators to form transcriptionally active complexes SIGNOR-255791 SIGNOR-FapBMP FAP: BMP MAPK14 protein Q16539 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates activity phosphorylation 10090 20551513 YES ggiuliani Mechanistic analysis revealed that the TAK1–MKK3/6–p38 MAPK axis phosphorylated Runx2, promoting its association with the coactivator CREB-binding protein (CBP), which was required to regulate osteoblast genetic programs. These findings reveal an in vivo function for p38β and establish that MAPK signaling is essential for bone formation in vivo. SIGNOR-255777 SIGNOR-FapBMP FAP: BMP MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Thr180 RHTDDEMtGYVATRW 9534 8622669 YES lperfetto These data indicate that mkk6 phosphorylates p38 map kinase on thr-180 and tyr-182, the sites of phosphorylation that activate p38 map kinase SIGNOR-40423 SIGNOR-FapBMP FAP: BMP MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr182 TDDEMTGyVATRWYR 9534 8622669 YES lperfetto These data indicate that mkk6 phosphorylates p38 map kinase on thr-180 and tyr-182, the sites of phosphorylation that activate p38 map kinase SIGNOR-40427 SIGNOR-FapBMP FAP: BMP MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 10480932 YES lperfetto We have found that p38 mitogen-activated protein kinase, and its direct activator MKK6 are rapidly activated in response to TGF-beta. SIGNOR-70607 SIGNOR-FapBMP FAP: BMP MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 20551513 YES ggiuliani Expression of a constitutively active mutant of MKK6 (MKK6-glu) (39), but not a kinase-inactive mutant of MKK6 (MKK6-K82A) (39), strongly promoted human MSC differentiation to osteoblasts as shown by increased ALP activity and extracellular matrix mineralization (Figure 4E). Furthermore, MKK6-glu‚Äìexpressing osteoblasts were treated with inhibitors of p38, JNK, and MEK (Figure 4F). Only treatment with the p38 inhibitor SB203580 blocked the effects of MKK6-glu. SIGNOR-255780 SIGNOR-FapGCC FAP: Glucocorticoids NfKb-p65/p50 complex SIGNOR-C13 SIGNOR HES1 protein Q14469 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0001938 24300895 NO These data indicate that basal NFκB activity at the conserved +26/+34 site of the HES1 gene promotes its expression, and that glucocorticoids can silence HES1 by inhibiting this activity. SIGNOR-253063 SIGNOR-FapGCC FAP: Glucocorticoids dexamethasone chemical CHEBI:41879 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 20956975 YES fspada Glucocorticoids, such as dexamethasone, have been used as in vitro inducers of adipogenesis. However, the roles of the glucocorticoid receptor (gr) in adipogenesis have not been well characterized yet. Here, we show that inhibition of gr activity using the gr antagonist ru486 prevents human mesenchymal stem cell and mouse embryonic fibroblast (mef) differentiation into adipocytes SIGNOR-168562 SIGNOR-FapGCC FAP: Glucocorticoids dexamethasone chemical CHEBI:41879 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 27660409 YES diabetic macular edema gcesareni They differ according to their glucocorticoid-receptor binding affinities (dexamethasone > triamcinolone > fluocinolone) and their lipophilicity (triamcinolone > fluocinolone > dexamethasone), characteristics that may partially explain their relative potencies SIGNOR-251694 SIGNOR-FapGCC FAP: Glucocorticoids AMPK complex SIGNOR-C15 SIGNOR FOXO1 protein Q12778 UNIPROT up-regulates phosphorylation 9606 18394876 YES lperfetto The energy sensor AMP-activated protein kinase (AMPK) has been shown to directly phosphorylate FoxO factors at six regulatory sites that are distinct from the Akt phosphorylation sites, resulting in FoxO activation. SIGNOR-216478 SIGNOR-FapGCC FAP: Glucocorticoids TNF protein P01375 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity 9606 8530143 NO andrea cerquone perpetuini Data from our laboratory demonstrate that the TNF signal transduction pathway-mediating NF-kappa B activation involves two phospholipases, a phosphatidylcholine-specific phospholipase C (PC-PLC) and an endosomal acidic sphingomyelinase (aSMase). The aSMase activation by TNF is secondary to the generation of 1,2-diacylglycerol (DAG) produced by a TNF-responsive PC-PLC. SMase and its product ceramide induce degradation of the NF-kappa B inhibitor I kappa B as well as NF-kappa B activation. SIGNOR-255689 SIGNOR-FapGCC FAP: Glucocorticoids SGK1 protein O00141 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 11154281 YES lperfetto Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. SIGNOR-249133 SIGNOR-FapGCC FAP: Glucocorticoids SGK1 protein O00141 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 11154281 YES lperfetto We show here that sgk1, like akt, promotes cell survival and that it does so in part by phosphorylating and inactivating fkhrl1. However, sgk and akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on fkhrl1. While both kinases can phosphorylate thr-32, sgk displays a marked preference for ser-315 whereas akt favors ser-253. SIGNOR-236607 SIGNOR-FapGCC FAP: Glucocorticoids SGK1 protein O00141 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 11154281 YES lperfetto Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. SIGNOR-249134 SIGNOR-FapGCC FAP: Glucocorticoids SGK1 protein O00141 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Thr24 LPRPRSCtWPLPRPE 10090 19965929 YES We demonstrate that SGK1 affects differentiation by direct phosphorylation of Foxo1, thereby changing its cellular localization from the nucleus to the cytosol. In addition we show that SGK1-/- cells are unable to relocalize Foxo1 to the cytosol in response to dexamethasone. SIGNOR-255925 SIGNOR-FapGCC FAP: Glucocorticoids TSC22D3 protein Q99576 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000011 12671681 NO In this study, we showed that GILZ, which is transcriptionally induced by GCs, inhibits the transcription of the PPAR-γ2 gene and blocks adipocyte differentiation SIGNOR-253296 SIGNOR-FapGCC FAP: Glucocorticoids FOXO1 protein Q12778 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 16670091 NO lperfetto FOXO1 coexpression dose-dependently repressed transcription from either the PPARgamma 1 or PPARgamma2 promoter reporter by 65%, whereas insulin (100 nm, 20-24 h) either partially or completely reversed this effect. SIGNOR-218013 SIGNOR-FapGCC FAP: Glucocorticoids HES1 protein Q14469 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates activity 9606 BTO:0001938 24300895 YES Altering the expression of HES1 did not obviously affect GR abundance (Figure 3A). However, genome-wide microarrays revealed that overexpression of HES1 resulted in inhibition of GR-mediated changes in the glucocorticoid regulated transcriptome, as compared to non-overexpressing controls SIGNOR-253064 SIGNOR-FapGCC FAP: Glucocorticoids HES1 protein Q14469 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 14614508 NO Overexpression of HES-1 fully repressed PPAR-g even in the presence of the ACREB inhibitor, showing that HES-1 acts downstream of CREB SIGNOR-254743 SIGNOR-FapGCC FAP: Glucocorticoids HES1 protein Q14469 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 BTO:0000011 16282371 NO Notch signaling blocks differentiation of 3T3-L1 preadipocytes, and this can be mimicked by constitutive expression of the Notch target gene Hes-1 SIGNOR-253058 SIGNOR-FapGCC FAP: Glucocorticoids PPARG protein P37231 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0004300 16150867 NO lperfetto Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor SIGNOR-256229 SIGNOR-FapGCC FAP: Glucocorticoids CEBPD protein P49716 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 10649448 NO gcesareni We conclude that glucocorticoid-induced adipogenesis from bone marrow stromal cells is mediated through a reaction cascade in which dexamethasone transcriptionally activates C/EBPdelta; C/EBPdelta then binds to PPARgamma2 promoter and transactivates PPARgamma2 gene expression. SIGNOR-253062 SIGNOR-FapGCC FAP: Glucocorticoids CEBPB protein P17676 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity transcriptional regulation 10090 16431920 YES fspada These data suggest that c/CEBP beta activates a single unified pathway of adipogenesis involving its stimulation of PPARgamma expression, which then activates C/EBP alpha expression by dislodging HDAC1 from the promoter for degradation in the proteasome SIGNOR-143952 SIGNOR-FapGCC FAP: Glucocorticoids NR3C1 protein P04150 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates binding 10116 18762022 YES The GR directly interferes with Hes1 promoter activity, triggering the recruitment of histone deacetylase (HDAC) activities to the Hes1 gene SIGNOR-253057 SIGNOR-FapGCC FAP: Glucocorticoids NR3C1 protein P04150 UNIPROT NFKBIA protein P25963 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7569975 NO andrea cerquone perpetuini Here it is shown that the synthetic glucocorticoid dexamethasone induces the transcription of the IKBc gene, which results in an increased rate of IKBa protein synthesis SIGNOR-255688 SIGNOR-FapGCC FAP: Glucocorticoids NR3C1 protein P04150 UNIPROT CEBPB protein P17676 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000746 27777311 NO We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα. SIGNOR-256117 SIGNOR-FapGCC FAP: Glucocorticoids NR3C1 protein P04150 UNIPROT CEBPB protein P17676 UNIPROT up-regulates activity binding 10116 9428795 YES We have shown that one of the functions of the GR to activate transcription of the AGP gene is to recruit C/EBPbeta and to maintain it bound at its target DNA sequences (SRU) SIGNOR-251655 SIGNOR-FapGCC FAP: Glucocorticoids NR3C1 protein P04150 UNIPROT CEBPB protein P17676 UNIPROT up-regulates activity binding 10090 BTO:0000011 11279134 YES lperfetto The differentiation of 3T3-L1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor gamma (PPARgamma) by dexamethasone (DEX), 3-isobutyl-1-methylxanthine (MIX), and insulin SIGNOR-250566 SIGNOR-FapGCC FAP: Glucocorticoids NR3C1 protein P04150 UNIPROT CEBPD protein P49716 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0000011 1840554 YES The expression levels of both C/EBPB and C/EBPD are increased dramatically during the time of hormonal stimulation (see Fig. 8). Furthermore, the C/EBPB- and C/EBPD encoding genes are activated directly by adipogenic hormones SIGNOR-251648 SIGNOR-FapGCC FAP: Glucocorticoids NR3C1 protein P04150 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates quantity transcriptional regulation 10090 22848740 YES miannu We show that FOXO3 is an immediate early glucocorticoid receptor (GR) target, whose transcription is even further enhanced by conditions that mimic metabolic stress. SIGNOR-255759 SIGNOR-FapGCC FAP: Glucocorticoids NR3C1 protein P04150 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000746 27777311 NO We observed GR binding on or near Cebpβ, Cebpδ, Klf5, Klf9, Cebpα, and Pparγ gene loci at 4 h but not at 0 h of adipogenesis. Thus, at least one of the mechanisms by which GR promotes adipogenesis in culture is by directly activating the expression of multiple adipogenic TFs. SIGNOR-256120 SIGNOR-FapGCC FAP: Glucocorticoids NR3C1 protein P04150 UNIPROT TSC22D3 protein Q99576 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001372 9430225 NO In thymocytes and peripheral T cells, GILZ gene expression is induced by DEX SIGNOR-253295 SIGNOR-FapGCC FAP: Glucocorticoids NR3C1 protein P04150 UNIPROT SGK1 protein O00141 UNIPROT up-regulates quantity transcriptional regulation 10116 15793248 NO We show here that dexamethasone upregulates transcription and expression of the serum- and glucocorticoid-inducible kinase 1 (SGK1) in insulin-secreting cells, an effect reversed by mifepristone (RU486), an antagonist of the nuclear glucocorticoid receptor. SIGNOR-255926 SIGNOR-FapGCC FAP: Glucocorticoids NFKBIA protein P25963 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 1340770 YES lperfetto Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b SIGNOR-217394 SIGNOR-FapGCC FAP: Glucocorticoids NFKBIA protein P25963 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 9914500 YES lperfetto In nonstimulated cells, nf-kappab is present in the cytosol where it is complexed to its inhibitor ikappab however, we found that only one of the activities, namely the ikk1/2 complex, exists as a pre-assembled kinase-substrate complex in which the ikks are directly or indirectly associated with several nf-kappab-related and ikappab-related proteins: rela, relb, crel, p100, p105, ikappa balpha, ikappa bbeta and ikappa bepsilon. SIGNOR-64092 SIGNOR-FapGCC FAP: Glucocorticoids HDAC1 protein Q13547 UNIPROT HES1 protein Q14469 UNIPROT down-regulates quantity transcriptional regulation 10090 18762022 NO These data suggest that the GR recruits cellular HDAC activities to the Hes1 promoter, thereby conferring transcriptional repression in response to GC signaling. SIGNOR-253054 SIGNOR-FapIBMXR FAP: IBMX/rosiglitazone 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKACA protein P17612 UNIPROT up-regulates chemical activation 9606 16293724 YES gcesareni Pge2 receptors are coupled to the G protein Gs, which causes accumulation of cyclic adenosine monophosphate (cAMP) and activates protein kinase a (PKA), we confirmed that PGE2 treatment or transfection of cells with the active catalytic subunit of PKA also stimulated the activity of a cAMP-responsive-element driven reporter gene (CRE-luc). SIGNOR-141786 SIGNOR-FapIBMXR FAP: IBMX/rosiglitazone 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKACA protein P17612 UNIPROT up-regulates chemical activation 9606 BTO:0000007 22863277 YES milica The cAMP signaling cascade can activate protein kinase a (PKA) SIGNOR-198492 SIGNOR-FapIBMXR FAP: IBMX/rosiglitazone rosiglitazone chemical CHEBI:50122 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation 9534 7768881 YES An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma) SIGNOR-251646 SIGNOR-FapIBMXR FAP: IBMX/rosiglitazone 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 ChEBI PDE1B protein Q01064 UNIPROT down-regulates activity chemical inhibition 9606 22014080 YES Until now, very few inhibitors of PDE1 were available for evaluating the contribution of PDE1 in tissue and cell function. Vinpocetine (Ahn et al., 1989) and 8-methoxymethyl-IBMX (Ahn et al., 1997) are common PDE1 inhibitors. SIGNOR-253400 SIGNOR-FapIBMXR FAP: IBMX/rosiglitazone 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 ChEBI PDE1C protein Q14123 UNIPROT down-regulates activity chemical inhibition 9606 22014080 YES Until now, very few inhibitors of PDE1 were available for evaluating the contribution of PDE1 in tissue and cell function. Vinpocetine (Ahn et al., 1989) and 8-methoxymethyl-IBMX (Ahn et al., 1997) are common PDE1 inhibitors. SIGNOR-253017 SIGNOR-FapIBMXR FAP: IBMX/rosiglitazone 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 ChEBI PDE1A protein P54750 UNIPROT down-regulates activity chemical inhibition 9606 22014080 YES Until now, very few inhibitors of PDE1 were available for evaluating the contribution of PDE1 in tissue and cell function. Vinpocetine (Ahn et al., 1989) and 8-methoxymethyl-IBMX (Ahn et al., 1997) are common PDE1 inhibitors. SIGNOR-256274 SIGNOR-FapIBMXR FAP: IBMX/rosiglitazone PDE1A protein P54750 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI down-regulates quantity chemical modification 9606 22014080 YES PDE1A and PDE1B preferentially hydrolyse cGMP, whereas PDE1C hydrolyses cAMP and cGMP with similar Km values SIGNOR-253398 SIGNOR-FapIBMXR FAP: IBMX/rosiglitazone PDE1C protein Q14123 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI down-regulates quantity chemical modification 9606 22014080 YES PDE1A and PDE1B preferentially hydrolyse cGMP, whereas PDE1C hydrolyses cAMP and cGMP with similar Km values SIGNOR-253399 SIGNOR-FapIBMXR FAP: IBMX/rosiglitazone CREB1 protein P16220 UNIPROT CEBPB protein P17676 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 14593102 NO lperfetto Expression of constitutively active CREB strongly activated C/EBPbeta promoter-reporter genes, induced expression of endogenous C/EBPbeta, and caused adipogenesis in the absence of the hormonal inducers normally required SIGNOR-250573 SIGNOR-FapIBMXR FAP: IBMX/rosiglitazone PPARG protein P37231 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0004300 16150867 NO lperfetto Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor SIGNOR-256229 SIGNOR-FapIBMXR FAP: IBMX/rosiglitazone PRKACA protein P17612 UNIPROT PPARG protein P37231 UNIPROT up-regulates activity 10090 BTO:0000011 20638365 NO Here we showed that cAMP-induced activation of protein kinase A (PKA) and Akt is essential for the transcriptional activation of PPAR-gamma SIGNOR-253019 SIGNOR-FapIBMXR FAP: IBMX/rosiglitazone PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001103 21902831 YES gcesareni Phosphorylation of CREB by PKA allows it to initiate the transcription of genes that contain a CRE element, two of which are PAX3 and MYF5. SIGNOR-176560 SIGNOR-FapIBMXR FAP: IBMX/rosiglitazone PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000669 15568017 YES gcesareni Using a combination of in vitro explant assays, mutant analysis and gene delivery into mouse embryos cultured ex vivo, we demonstrate that adenylyl cyclase signalling via PKA and its target transcription factor CREB are required for WNT-directed myogenic gene expression. SIGNOR-131307 SIGNOR-FapIBMXR FAP: IBMX/rosiglitazone CEBPB protein P17676 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity transcriptional regulation 10090 16431920 YES fspada These data suggest that c/CEBP beta activates a single unified pathway of adipogenesis involving its stimulation of PPARgamma expression, which then activates C/EBP alpha expression by dislodging HDAC1 from the promoter for degradation in the proteasome SIGNOR-143952 SIGNOR-FapIBMXR FAP: IBMX/rosiglitazone ADCY1 protein Q08828 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates chemical modification 9606 17251915 YES gcesareni Typically Gas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate many molecules, including phospholipases, ion channels and lipid kinases. SIGNOR-152546 SIGNOR-FapIBMXR FAP: IBMX/rosiglitazone ADCY1 protein Q08828 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates chemical modification 9606 22863277 YES milica To further explore the role of camp signaling in the hippo pathway, we treated cells with forskolin, an activator of adenylyl cyclase that results in cAMP production. SIGNOR-198486 SIGNOR-FapIL4 FAP: IL4/IL13 induction JAK2 protein O60674 UNIPROT STAT6 protein P42226 UNIPROT up-regulates activity phosphorylation 9606 9852261 YES gcesareni Stat6 activation is mediated through jak1 and jak2 tyrosine kinases. SIGNOR-62585 SIGNOR-FapIL4 FAP: IL4/IL13 induction PPARG protein P37231 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0004300 16150867 NO lperfetto Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor SIGNOR-256229 SIGNOR-FapIL4 FAP: IL4/IL13 induction STAT6 protein P42226 UNIPROT PPARG protein P37231 UNIPROT down-regulates activity 10090 24948596 NO IL-4 was shown to inhibit lipid accumulation in adipose tissue by a mechanism that includes activation of Stat6, which suppresses PPARα transcriptional activity SIGNOR-254682 SIGNOR-FapIL4 FAP: IL4/IL13 induction JAK1 protein P23458 UNIPROT STAT6 protein P42226 UNIPROT up-regulates activity phosphorylation 9606 9852261 YES gcesareni Stat6 activation is mediated through jak1 and jak2 tyrosine kinases SIGNOR-62582 SIGNOR-FapIL4 FAP: IL4/IL13 induction JAK1 protein P23458 UNIPROT STAT6 protein P42226 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 23124025 YES lperfetto IL-4-stimulated Stat6 activation is mediated by Jak1 whereas Tyk2 is required for Stat6 activation in IL-13-treated monocytes SIGNOR-249531 SIGNOR-FapIL4 FAP: IL4/IL13 induction IL4 protein P05112 UNIPROT IL4R protein P24394 UNIPROT up-regulates activity binding 9606 BTO:0000801 18852293 YES lperfetto IL-4 signals through the type I (IL-4Ralpha/common gamma-chain [gammac]) and the type II (IL-4Ralpha/-13Ralpha1) IL-4 receptors, whereas IL-13 utilizes only the type II receptor. SIGNOR-249527 SIGNOR-FapIL4 FAP: IL4/IL13 induction IL4 protein P05112 UNIPROT IL4R protein P24394 UNIPROT up-regulates binding -1 10219247 YES gcesareni Nterleukin-4 (il-4) is a principal regulatory cytokine during an immune response and a crucial determinant for allergy and asthma. Il-4 binds with high affinity and specificity to the ectodomain of the il-4 receptor alpha chain (il4-bp). SIGNOR-67217 SIGNOR-FapIL4 FAP: IL4/IL13 induction IL4 protein P05112 UNIPROT IL4R protein P24394 UNIPROT up-regulates binding 9606 12704343 YES milica IL-4R Is a 140-kd protein that binds il-4 with high affinity SIGNOR-100762 SIGNOR-FapIL4 FAP: IL4/IL13 induction IL13 protein P35225 UNIPROT IL4R protein P24394 UNIPROT up-regulates binding 9606 12704343 YES milica Both il-4 and il-13 use the IL-4R Chain as a component of their receptors. SIGNOR-100753 SIGNOR-FapIL4 FAP: IL4/IL13 induction IL4R protein P24394 UNIPROT JAK1 protein P23458 UNIPROT up-regulates 9606 7538655 NO lperfetto We demonstrate that il4r triggering induced the tyrosine phosphorylation of jak3 SIGNOR-34756 SIGNOR-FapIL4 FAP: IL4/IL13 induction IL4R protein P24394 UNIPROT JAK1 protein P23458 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 23124025 YES lperfetto Although the receptor-associated tyrosine kinases Jak2 and Tyk2 are activated after the recruitment of IL-13 to its receptor (containing IL-4R and IL-13R1), IL-4 stimulates Jak1 activation. SIGNOR-249529 SIGNOR-FapIL4 FAP: IL4/IL13 induction IL4R protein P24394 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 YES milica IL-4Rα, γc, and IL-13Rα1 all contain proline-rich box-1 regions that bind jak1, jak3, and tyk2, respectively. Il-4 uses the type ii receptor, and IL-13R1 Binds tyk2. Il-13 results in activation of jak1 and tyk2 in hematopoietic and nonhematopoietic cells. SIGNOR-100774 SIGNOR-FapIL4 FAP: IL4/IL13 induction IL4R protein P24394 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 18852293 YES lperfetto Downstream intracellular signaling from the IL-4IL-4Rc complex involves activation of the Jak1 and Jak3 kinases, phosphorylation of the Stat6 transcription factor, and activation of the insulin receptor substrate (IRS)-2 and Dok2-signaling intermediates. IL-13 initially binds to IL-13R1 with intermediate affinity, and then heterodimerizes with IL-4R. The IL-13IL-13R1IL-4R complex activates the Tyk2, Jak2, and Jak1 kinases and Stat6. SIGNOR-249530 SIGNOR-FapNOTCH FAP: Notch RBPJ/NOTCH complex SIGNOR-C97 SIGNOR HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7566092 YES lperfetto Here we show that activated forms of mNotch associate with the human analogue of Su(H), KBF2/RBP-J kappa (refs 8,9) and act as transcriptional activators through the KBF2-binding sites of the HES-1 promoter. SIGNOR-209590 SIGNOR-FapNOTCH FAP: Notch gamma-secretase complex SIGNOR-C98 SIGNOR NOTCH1 protein P46531 UNIPROT up-regulates activity cleavage 9606 25610395 YES lperfetto The membrane-bound Notch segment that results from this cleavage, known as Notch Intracellular Truncation domain (NEXT), is a γ-secretase substrate. γ-Secretase performs the subsequent cleavage at S3, releasing Notch intracellular domain (NICD) from the membrane and allowing for signal transduction through binding with the CBL-1, Su(H), Lag-1 family of DNA binding proteins. SIGNOR-209717 SIGNOR-FapNOTCH FAP: Notch rosiglitazone chemical CHEBI:50122 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation 9534 7768881 YES An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma) SIGNOR-251646 SIGNOR-FapNOTCH FAP: Notch DLL1 protein O00548 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 9606 BTO:0000776 16140393 YES lperfetto Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate. SIGNOR-209732 SIGNOR-FapNOTCH FAP: Notch CREB1 protein P16220 UNIPROT CEBPB protein P17676 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 14593102 NO lperfetto Expression of constitutively active CREB strongly activated C/EBPbeta promoter-reporter genes, induced expression of endogenous C/EBPbeta, and caused adipogenesis in the absence of the hormonal inducers normally required SIGNOR-250573 SIGNOR-FapNOTCH FAP: Notch HES1 protein Q14469 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19129776 YES gcesareni HES1 binding to the promoter of the NC3C1 gene inhibits its expression and results in insufficient production of the encoded glucocorticoid receptor- rendering these cells resistant to treatment with dexamethasone SIGNOR-251674 SIGNOR-FapNOTCH FAP: Notch HES1 protein Q14469 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates activity 9606 BTO:0001938 24300895 YES Altering the expression of HES1 did not obviously affect GR abundance (Figure 3A). However, genome-wide microarrays revealed that overexpression of HES1 resulted in inhibition of GR-mediated changes in the glucocorticoid regulated transcriptome, as compared to non-overexpressing controls SIGNOR-253064 SIGNOR-FapNOTCH FAP: Notch HES1 protein Q14469 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000759 14614508 YES CREB inhibits hepatic PPAR-gamma expression in the fasted state by stimulating the expression of the Hairy Enhancer of Split (HES-1) gene, a transcriptional repressor that is shown here to be a mediator of fasting lipid metabolism in vivo SIGNOR-253584 SIGNOR-FapNOTCH FAP: Notch HES1 protein Q14469 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR down-regulates activity binding 10090 BTO:0000562 16682003 YES lperfetto Here we show that hrt2 and hes1 interact with rbp-jkappa to negatively regulate notch-dependent activation of hrt and hes expression. SIGNOR-209756 SIGNOR-FapNOTCH FAP: Notch PPARG protein P37231 UNIPROT CEBPA protein P49715 UNIPROT up-regulates activity transcriptional regulation 10090 BTO:0002572;BTO:0000011;BTO:0005065 16431920 NO Dislodging hdac1 from the promoter lperfetto These data suggest that c/ebp beta activates a single unified pathway of adipogenesis involving its stimulation of ppargamma expression, which then activates c/ebp alpha expression by dislodging hdac1 from the promoter for degradation in the proteasome SIGNOR-235358 SIGNOR-FapNOTCH FAP: Notch PPARG protein P37231 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0004300 16150867 NO lperfetto Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor SIGNOR-256229 SIGNOR-FapNOTCH FAP: Notch GATA2 protein P23769 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 11021798 NO fspada Constitutive gata-2 and gata-3 expression suppressed adipocyte differentiation and trapped cells at the preadipocyte stage. SIGNOR-78659 SIGNOR-FapNOTCH FAP: Notch CEBPD protein P49716 UNIPROT KLF5 protein Q13887 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16054042 NO fspada Klf5 expression is induced by c/ebpbeta and delta. KLF5, in turn, acts in concert with c/ebpbeta/delta to activate the ppargamma2 promoter. SIGNOR-210007 SIGNOR-FapNOTCH FAP: Notch CEBPB protein P17676 UNIPROT KLF5 protein Q13887 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16054042 NO fspada Klf5 expression is induced by c/ebpbeta and delta. KLF5, in turn, acts in concert with c/ebpbeta/delta to activate the ppargamma2 promoter. SIGNOR-210004 SIGNOR-FapNOTCH FAP: Notch CEBPB protein P17676 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity transcriptional regulation 10090 16431920 YES fspada These data suggest that c/CEBP beta activates a single unified pathway of adipogenesis involving its stimulation of PPARgamma expression, which then activates C/EBP alpha expression by dislodging HDAC1 from the promoter for degradation in the proteasome SIGNOR-143952 SIGNOR-FapNOTCH FAP: Notch CEBPA protein P49715 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0000011 25451943 NO gcesareni Adipogenesis is controlled by a transcriptional cascade composed of a large number of transcriptional factors, among which CCAAT/enhancer-binding protein (C/EBP) ² plays an essential role. SIGNOR-250562 SIGNOR-FapNOTCH FAP: Notch KLF5 protein Q13887 UNIPROT PPARG protein P37231 UNIPROT up-regulates transcriptional regulation 10090 16054042 NO fspada Klf5 expression is induced by c/ebpbeta and delta. KLF5, in turn, acts in concert with c/ebpbeta/delta to activate the ppargamma2 promoter. SIGNOR-210010 SIGNOR-FapNOTCH FAP: Notch NOTCH1 protein P46531 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding 9606 7566092 YES Here we show that activated forms of mNotch associate with the human analogue of Su(H), KBF2/RBP-Jk and act as transcriptional activators through the KBF2-binding sites of the HES-1 promoter. SIGNOR-254381 SIGNOR-FapNOTCH FAP: Notch NR3C1 protein P04150 UNIPROT CEBPB protein P17676 UNIPROT up-regulates activity binding 10116 9428795 YES We have shown that one of the functions of the GR to activate transcription of the AGP gene is to recruit C/EBPbeta and to maintain it bound at its target DNA sequences (SRU) SIGNOR-251655 SIGNOR-FapNOTCH FAP: Notch NR3C1 protein P04150 UNIPROT CEBPB protein P17676 UNIPROT up-regulates activity binding 10090 BTO:0000011 11279134 YES lperfetto The differentiation of 3T3-L1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor gamma (PPARgamma) by dexamethasone (DEX), 3-isobutyl-1-methylxanthine (MIX), and insulin SIGNOR-250566 SIGNOR-FapNOTCH FAP: Notch NR3C1 protein P04150 UNIPROT CEBPD protein P49716 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0000011 1840554 YES The expression levels of both C/EBPB and C/EBPD are increased dramatically during the time of hormonal stimulation (see Fig. 8). Furthermore, the C/EBPB- and C/EBPD encoding genes are activated directly by adipogenic hormones SIGNOR-251648 SIGNOR-FapPDGFRA FAP: PDGFR alpha imatinib chemical CHEBI:45783 ChEBI PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition 9606 22045730 YES Recently, imatinib, an inhibitor of several tyrosine kinases, including c-abl, c-kit and PDGFRs, was demonstrated to ameliorate dystrophic phenotypes in mdx mice by suppressing the phosphorylation of PDGFRa SIGNOR-254378 SIGNOR-FapPDGFRA FAP: PDGFR alpha ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 18483217 NO PDGF signaling has been implicated in several fibrotic conditions and is assumed to play a role in driving proliferation of cells with a myofibroblast phenotype. SIGNOR-254373 SIGNOR-FapPDGFRA FAP: PDGFR alpha ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 NO Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases. SIGNOR-254374 SIGNOR-FapPDGFRA FAP: PDGFR alpha PDGFA protein P04085 UNIPROT PDGFRA protein P16234 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0000763 11803579 YES gcesareni Platelet-derived growth factors (pdgf) constitute a family of four gene products (pdgf-a-d) acting by means of two receptor tyrosine kinases, pdgfr alpha and beta. Three of the ligands (pdgf-a, -b, and -c) bind to pdgfr alpha with high affinity. SIGNOR-114268 SIGNOR-FapPDGFRA FAP: PDGFR alpha PDGFB protein P01127 UNIPROT PDGFRA protein P16234 UNIPROT up-regulates activity binding 9606 11331882 YES miannu Pdgf-b activates both pdgfr-alpha and pdgfr-beta SIGNOR-107397 SIGNOR-FapPDGFRA FAP: PDGFR alpha AKT1 protein P31749 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 18483217 NO PDGF signaling has been implicated in several fibrotic conditions and is assumed to play a role in driving proliferation of cells with a myofibroblast phenotype. SIGNOR-254371 SIGNOR-FapPDGFRA FAP: PDGFR alpha AKT1 protein P31749 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 NO Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases. SIGNOR-254372 SIGNOR-FapPDGFRA FAP: PDGFR alpha PDGFRA protein P16234 UNIPROT PDGFRA protein P16234 UNIPROT up-regulates activity phosphorylation Tyr1018 RLSADSGyIIPLPDI 9823 BTO:0004007 7535778 YES miannu We have identified two autophosphorylation sites, Tyr-988 and Tyr-1018, in the platelet-derived growth factor (PDGF) alpha-receptor carboxyl-terminal tail, which are involved in binding of phospholipase C-gamma (PLC-gamma). We conclude that phosphorylated Tyr-988 and Tyr-1018 in the PDGF α-receptor carboxyl-terminal tail bind PLC-γ, but this association leads to only a relatively low level of tyrosine phosphorylation and activation of PLC-γ. SIGNOR-250250 SIGNOR-FapPDGFRA FAP: PDGFR alpha PDGFRA protein P16234 UNIPROT PDGFRA protein P16234 UNIPROT up-regulates activity phosphorylation Tyr762 SDIQRSLyDRPASYK 9823 9546424 YES miannu Tyr-762 is an autophosphorylation site in the human platelet-derived growth factor (PDGF) alpha-receptor. Crk proteins associate with phosphorylated Tyr-762 in the PDGF a-receptor in vivo SIGNOR-249716 SIGNOR-FapPDGFRA FAP: PDGFR alpha PDGFRA protein P16234 UNIPROT PDGFRA protein P16234 UNIPROT up-regulates activity phosphorylation Tyr988 RVDSDNAyIGVTYKN 9823 BTO:0004007 7535778 YES miannu We have identified two autophosphorylation sites, Tyr-988 and Tyr-1018, in the platelet-derived growth factor (PDGF) alpha-receptor carboxyl-terminal tail, which are involved in binding of phospholipase C-gamma (PLC-gamma). We conclude that phosphorylated Tyr-988 and Tyr-1018 in the PDGF α-receptor carboxyl-terminal tail bind PLC-γ, but this association leads to only a relatively low level of tyrosine phosphorylation and activation of PLC-γ. SIGNOR-250252 SIGNOR-FapPDGFRA FAP: PDGFR alpha PDGFRA protein P16234 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 9606 24743741 NO To further investigate the signaling pathway through which PDGFRα promotes the proliferation of PDGFRα+ cells, we used inhibitors of PI3K-Akt and Ras-MAPK pathways, which are known to be downstream signaling pathways of PDGFRα SIGNOR-254376 SIGNOR-FapPDGFRA FAP: PDGFR alpha PDGFRA protein P16234 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 24743741 NO To further investigate the signaling pathway through which PDGFRαpromotes the proliferation of PDGFRα+ cells, we used inhibitors of PI3K-Akt and Ras-MAPK pathways, which are known to be downstream signaling pathways of PDGFRα. Thus, both PI3K-Akt and MEK2-MAPK pathways are necessary for PDGFRα-driven proliferation. SIGNOR-254377 SIGNOR-FapSHH FAP: SHH SMO protein Q99835 UNIPROT GATA2 protein P23769 UNIPROT up-regulates activity 10090 BTO:0000011 16399502 NO fferrentino In mammalian models [...] Hh signaling also inhibits mammalian adipogenesis. Hh signals elicit this function early in adipogenesis, upstream of PPARγ, potentially diverting preadipocytes as well as multipotent mesenchymal prescursors away from adipogenesis and toward osteogenesis. Hh may elicit these effects by inducing the expression of antiadipogenic transcription factors such as Gata2. SIGNOR-251656 SIGNOR-FapSHH FAP: SHH SMO protein Q99835 UNIPROT TIMP3 protein P35625 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 28709001 NO We identified that ciliary Hh signaling in FAPs regulates expression of Timp3. Future experiments will determine whether Timp3 is a direct or indirect target of Hh signaling. SIGNOR-255907 SIGNOR-FapSHH FAP: SHH SMO protein Q99835 UNIPROT GATA3 protein P23771 UNIPROT up-regulates activity 17139329 YES fferrentino That GATA is a downstream effector of the hedgehog pathway. SIGNOR-253527 SIGNOR-FapSHH FAP: SHH PTCH1 protein Q13635 UNIPROT SMO protein Q99835 UNIPROT down-regulates activity binding 9606 BTO:0001757;BTO:0001298 12192414 YES lperfetto We show that free Ptc (unbound by Hh) acts sub-stoichiometrically to suppress Smo activity and thus is critical in specifying the level of pathway activity. SIGNOR-91709 SIGNOR-FapSHH FAP: SHH PPARG protein P37231 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0004300 16150867 NO lperfetto Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor SIGNOR-256229 SIGNOR-FapSHH FAP: SHH GATA3 protein P23771 UNIPROT CEBPB protein P17676 UNIPROT down-regulates binding 10090 15632071 YES fspada In the present study, we demonstrate that both gata-2 and gata-3 form protein complexes with ccaat/enhancer binding protein alpha (c/ebpalpha) and c/ebpbeta, members of a family of transcription factors that are integral to adipogenesis. []the interaction between gata and c/ebp factors is critical for the ability of gata to suppress adipocyte differentiation. SIGNOR-132952 SIGNOR-FapSHH FAP: SHH GATA3 protein P23771 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 15632071 NO fspada Constitutive expression of both gata-2 and gata-3 suppressed adipocyte differentiation, partially through direct binding to the peroxisome proliferator-activated receptor gamma (ppargamma) promoter and suppression of its basal activity SIGNOR-132955 SIGNOR-FapSHH FAP: SHH TIMP3 protein P35625 UNIPROT MMP14 protein P50281 UNIPROT down-regulates activity binding 10090 BTO:0005300 28709001 YES FAP cilia regulated the expression of TIMP3, a secreted metalloproteinase inhibitor, that inhibited MMP14 to block adipogenesis. SIGNOR-255908 SIGNOR-FapSHH FAP: SHH GATA2 protein P23769 UNIPROT PPARG protein P37231 UNIPROT down-regulates activity 9606 20510530 YES fferrentino GATA2 interacts directly with PPARG and C/EBP a , which may deplete PPARG involved in the promotion of adipogenesis SIGNOR-132949 SIGNOR-FapSHH FAP: SHH CEBPB protein P17676 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity transcriptional regulation 10090 16431920 YES fspada These data suggest that c/CEBP beta activates a single unified pathway of adipogenesis involving its stimulation of PPARgamma expression, which then activates C/EBP alpha expression by dislodging HDAC1 from the promoter for degradation in the proteasome SIGNOR-143952 SIGNOR-FapSHH FAP: SHH CEBPB protein P17676 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 11884404 NO fferrentino Overexpression and ribozyme-mediated targeting of transcriptional coactivators CREB-binding protein and p300 revealed their indispensable roles in adipocyte differentiation through the regulation of peroxisome proliferator-activated receptor gamma. SIGNOR-250564 SIGNOR-FapSHH FAP: SHH CEBPB protein P17676 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0000011 25451943 NO gcesareni Adipogenesis is controlled by a transcriptional cascade composed of a large number of transcriptional factors, among which CCAAT/enhancer-binding protein (C/EBP) β plays an essential role. SIGNOR-238297 SIGNOR-FapSHH FAP: SHH SHH protein Q15465 UNIPROT PTCH1 protein Q13635 UNIPROT down-regulates activity binding 9606 14556242 YES lperfetto In the responding cell, active Hedgehog binds to its receptor Patched, a 12-pass transmembrane protein, which frees Smoothened, an adjacent 7-pass transmembrane protein, for downstream signaling.Thus, a balance is created by the antagonism of Hedgehog and Patched, whose relative concentrations alternate with respect to each other. SIGNOR-118615 SIGNOR-FapSHH FAP: SHH SHH protein Q15465 UNIPROT PTCH1 protein Q13635 UNIPROT down-regulates activity binding 9606 15618519 YES lperfetto Binding of sonic hedgehog (shh) to patched (ptc) relieves the latter's tonic smoothened (smo), a receptor that spans the cell membrane seven times. .Ptch Exists in vertebrates as two isoforms, ptch1 and ptch2, which seem to be equivalent in terms of binding the three hh isoforms. SIGNOR-132675 SIGNOR-FapSHH FAP: SHH SHH protein Q15465 UNIPROT PTCH1 protein Q13635 UNIPROT down-regulates activity binding 9606 BTO:0001253 9811851 YES lperfetto Biochemical analysis of ptch and ptch2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with smo.Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH. SIGNOR-61552 SIGNOR-FapSHH FAP: SHH MMP14 protein P50281 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 28709001 NO MMP14 Promotes Adipogenesis Downstream of or in Parallel to TIMP3 SIGNOR-255909 SIGNOR-FapSIR FAP: SIRT1 SRT1720 chemical CID:25232708 ChEBI SIRT1 protein Q96EB6 UNIPROT up-regulates activity chemical activation 9606 18046409 YES Selleck gcesareni Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. SIGNOR-207114 SIGNOR-FapSIR FAP: SIRT1 resveratrol chemical CHEBI:27881 ChEBI SIRT1 protein Q96EB6 UNIPROT up-regulates activity chemical activation -1 12939617 YES gcesareni We show that the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD(+), and increases cell survival by stimulating SIRT1-dependent deacetylation of p53 SIGNOR-238786 SIGNOR-FapSIR FAP: SIRT1 SIRT1 protein Q96EB6 UNIPROT NCOR2 protein Q9Y618 UNIPROT up-regulates 9606 22395773 YES FFerrentino In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription. SIGNOR-253506 SIGNOR-FapSIR FAP: SIRT1 SIRT1 protein Q96EB6 UNIPROT NCOR1 protein O75376 UNIPROT up-regulates 9606 22395773 YES FFerrentino In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription. SIGNOR-253505 SIGNOR-FapSIR FAP: SIRT1 SIRT1 protein Q96EB6 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity deacetylation 10090 BTO:0002572 27776347 YES SIRT1 deacetylates β-catenin to promote its accumulation in the nucleus and thus induces the transcription of genes that block MSC adipogenesis. SIGNOR-256208 SIGNOR-FapSIR FAP: SIRT1 SIRT1 protein Q96EB6 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates activity deacetylation 9606 BTO:0001103 22395773 YES lperfetto SIRT1 controls the acetylation of FOXO transcription factors, which are important regulators of lipid and glucose metabolism as well as stress response. On the other hand, SIRT1 can also stimulate the gluconeogenic transcriptional program by deacetylating and activating FOXO1. SIGNOR-253509 SIGNOR-FapSIR FAP: SIRT1 FOXO1 protein Q12778 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 16670091 NO lperfetto FOXO1 coexpression dose-dependently repressed transcription from either the PPARgamma 1 or PPARgamma2 promoter reporter by 65%, whereas insulin (100 nm, 20-24 h) either partially or completely reversed this effect. SIGNOR-218013 SIGNOR-FapSIR FAP: SIRT1 PPARG protein P37231 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0004300 16150867 NO lperfetto Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor SIGNOR-256229 SIGNOR-FapSIR FAP: SIRT1 CTNNB1 protein P35222 UNIPROT PPARG protein P37231 UNIPROT down-regulates 9606 BTO:0000222 10937998 NO fspada Wnt-10b, is a molecular switch that governs adipogenesis. Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma). SIGNOR-80592 SIGNOR-FapSIR FAP: SIRT1 NCOR1 protein O75376 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22395773 YES FFerrentino In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription. SIGNOR-253507 SIGNOR-FapSIR FAP: SIRT1 NCOR2 protein Q9Y618 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22395773 YES FFerrentino In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription. SIGNOR-253508 SIGNOR-FapTGFB FAP: TGF beta SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR CEBPB protein P17676 UNIPROT down-regulates activity transcriptional regulation 9606 17139329 YES fferrentino Phosphorylation of receptor-regulated SMADs (for example, SMAD1 or SMAD3) stimulates dimer formation with SMAD4 and translocation to the nucleus, where the SMADs regulate the transcription of target gene SMAD3 binds to C/EBPs and inhibits their transcriptional activity, including their ability to transactivate the Pparg2 promoter SIGNOR-253538 SIGNOR-FapTGFB FAP: TGF beta SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR PPARG protein P37231 UNIPROT down-regulates activity 9606 17139329 NO fferrentino Phosphorylation of receptor-regulated SMADs (for example, SMAD1 or SMAD3) stimulates dimer formation with SMAD4 and translocation to the nucleus, where the SMADs regulate the transcription of target gene SMAD3 binds to C/EBPs and inhibits their transcriptional activity, including their ability to transactivate the Pparg2 promoter SIGNOR-253537 SIGNOR-FapTGFB FAP: TGF beta SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 24877152 NO Conversely, a reduced amount of IGF-1R diminished the levels of P-AKT, allowing dissociation and nuclear translocation of Smad3 and enhancement of the TGFŒ≤1 signaling pathway and fibrosis SIGNOR-254375 SIGNOR-FapTGFB FAP: TGF beta TRAF6 protein Q9Y4K3 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity ubiquitination Lys34 NFEEIDYkEIEVEEV 9606 18758450 YES lperfetto Intriguingly, TGF-beta-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6. SIGNOR-236071 SIGNOR-FapTGFB FAP: TGF beta TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity binding 9606 22326956 YES lperfetto TGF-beta signaling mediates a wide range of biological activities in development and disease. TGF-beta ligands signal through heterodimeric type I and type II receptors (TGF-beta receptor type I [TbetaRI, also known as ALK5 and TGFBR1] and TbetaRII) that are members of the serine/threonine kinase family. SIGNOR-196022 SIGNOR-FapTGFB FAP: TGF beta TGFB1 protein P01137 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates activity binding 9534 BTO:0004055 1310899 YES lperfetto A cdna encoding the tgf-beta type ii receptor protein has been isolated by an expression cloning strategy. The cloned cdna, when transfected into cos cells, leads to overexpression of an approximately 80 kd protein that specifically binds radioiodinated tgf-beta 1. Excess tgf-beta 1 competes for binding of radioiodinated tgf-beta 1 in a dose-dependent manner and is more effective than tgf-beta 2. SIGNOR-236080 SIGNOR-FapTGFB FAP: TGF beta TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity phosphorylation Thr200 LPLLVQRtIARTIVL 452646 7774578 YES lperfetto The tgf-beta type ii receptor (t beta r-ii) is a transmembrane serine/threonine kinase that, upon ligand binding, recruits and phosphorylates a second transmembrane kinase, t beta r-i, as a requirement for signal transduction. In contrast to the relatively innocuous nature of single site mutations in the ttsgsgsg sequence, mutation of thr200 or 204 to valine causes marked losses in ligand-induced phosphorylation and signaling. SIGNOR-32744 SIGNOR-FapTGFB FAP: TGF beta TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity phosphorylation Thr204 VQRTIARtIVLQESI 452646 7774578 YES lperfetto The TGF-beta type II receptor (T beta R-II) is a transmembrane serine/threonine kinase that, upon ligand binding, recruits and phosphorylates a second transmembrane kinase, T beta R-I, as a requirement for signal transduction. In contrast to the relatively innocuous nature of single site mutations in the ttsgsgsg sequence, mutation of thr200 or 204 to valine causes marked losses in ligand-induced phosphorylation and signaling. SIGNOR-32748 SIGNOR-FapTGFB FAP: TGF beta TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity phosphorylation Thr176 PFISEGTtLKDLIYD -1 8576253 YES giulio giuliani From our present data, it is not easy to deduce the mechanistic significance of serine 172 and threonine 176 of TŒ≤R-I in TGF-Œ≤ signaling. Although it was reported that TGF-Œ≤-induced phosphorylation of these residues was not detected in vivo(22), it is still possible that TŒ≤R-II may phosphorylate these residues as minor phosphorylation site(s). SIGNOR-255961 SIGNOR-FapTGFB FAP: TGF beta TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity phosphorylation Thr200 LPLLVQRtIARTIVL -1 8576253 YES giulio giuliani From our present data, it is not easy to deduce the mechanistic significance of serine 172 and threonine 176 of TŒ≤R-I in TGF-Œ≤ signaling. Although it was reported that TGF-Œ≤-induced phosphorylation of these residues was not detected in vivo(22), it is still possible that TŒ≤R-II may phosphorylate these residues as minor phosphorylation site(s). SIGNOR-255962 SIGNOR-FapTGFB FAP: TGF beta SMAD3 protein P84022 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR form complex binding 9606 9843571 YES lperfetto TGF-beta treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. SIGNOR-229557 SIGNOR-FapTGFB FAP: TGF beta MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9534 7839144 YES lperfetto Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. SIGNOR-232156 SIGNOR-FapTGFB FAP: TGF beta MAP3K7 protein O43318 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 11460167 YES lperfetto The activity of tak1 to phosphorylate mkk6, which activates the jnk-p38 kinase pathway, is directly regulated by k63-linked polyubiquitination SIGNOR-109497 SIGNOR-FapTGFB FAP: TGF beta MAP3K7 protein O43318 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000222 21902831 YES lperfetto TAK1 can phosphorylate and activate MAP kinase kinase 3/6 (MKK3/6), and numerous studies have demonstrated a requirement for MKK3/6 activity in the initiation of myoblast differentiation, again in a p38-dependent manner. SIGNOR-236093 SIGNOR-FapTGFB FAP: TGF beta PPARG protein P37231 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0004300 16150867 NO lperfetto Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor SIGNOR-256229 SIGNOR-FapTGFB FAP: TGF beta CEBPB protein P17676 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0000011 25451943 NO gcesareni Adipogenesis is controlled by a transcriptional cascade composed of a large number of transcriptional factors, among which CCAAT/enhancer-binding protein (C/EBP) β plays an essential role. SIGNOR-238297 SIGNOR-FapTGFB FAP: TGF beta TGFBR1 protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser423 SPSIRCSsVS 10090 BTO:0005493;BTO:0000165 19458083 YES lperfetto A major event leading to smad3 activation is the tgf-beta-induced, tbetari-mediated phosphorylation at two c-terminal serine residues, ser-423 and ser-425, which triggers dissociation of smad3 from its receptors to form a complex with smad4 and accumulate in the nucleus SIGNOR-235385 SIGNOR-FapTGFB FAP: TGF beta TGFBR1 protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser425 SIRCSSVs 10090 BTO:0005493;BTO:0000165 19458083 YES lperfetto A major event leading to Smad3 activation is the TGF-beta-induced, TbetaRI-mediated phosphorylation at two C-terminal serine residues, Ser-423 and Ser-425, which triggers dissociation of Smad3 from its receptors to form a complex with Smad4 and accumulate in the nucleus SIGNOR-235380 SIGNOR-FapTGFB FAP: TGF beta TGFBR1 protein P36897 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0002181 18758450 YES lperfetto Here we report that the ubiquitin ligase (e3) traf6 interacts with a consensus motif present in tbetari. The tbetari-traf6 interaction is required for tgf-beta-induced autoubiquitylation of traf6 and subsequent activation of the tak1-p38/jnk pathway, which leads to apoptosis. SIGNOR-236119 SIGNOR-FapTGFB FAP: TGF beta TGFBR1 protein P36897 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0000007 18922473 YES gcesareni We report here that TRAF6 is specifically required for the Smad-independent activation of JNK and p38 and its carboxyl TRAF homology domain physically interacts with TGF-² receptors SIGNOR-241918 SIGNOR-FapTGFB FAP: TGF beta MAPK14 protein Q16539 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates transcriptional regulation 10116 11904165 NO ggiuliani These data indicate that TGF-beta1-induced p38 activation is involved in TGF-beta1-stimulated collagen synthesis. SIGNOR-255958 SIGNOR-FapTGFB FAP: TGF beta MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 20551513 YES ggiuliani Expression of a constitutively active mutant of MKK6 (MKK6-glu) (39), but not a kinase-inactive mutant of MKK6 (MKK6-K82A) (39), strongly promoted human MSC differentiation to osteoblasts as shown by increased ALP activity and extracellular matrix mineralization (Figure 4E). Furthermore, MKK6-glu‚Äìexpressing osteoblasts were treated with inhibitors of p38, JNK, and MEK (Figure 4F). Only treatment with the p38 inhibitor SB203580 blocked the effects of MKK6-glu. SIGNOR-255780 SIGNOR-FapTGFB FAP: TGF beta MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Thr180 RHTDDEMtGYVATRW 9534 8622669 YES lperfetto These data indicate that mkk6 phosphorylates p38 map kinase on thr-180 and tyr-182, the sites of phosphorylation that activate p38 map kinase SIGNOR-40423 SIGNOR-FapTGFB FAP: TGF beta MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr182 TDDEMTGyVATRWYR 9534 8622669 YES lperfetto These data indicate that mkk6 phosphorylates p38 map kinase on thr-180 and tyr-182, the sites of phosphorylation that activate p38 map kinase SIGNOR-40427 SIGNOR-FapTGFB FAP: TGF beta MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 10480932 YES lperfetto We have found that p38 mitogen-activated protein kinase, and its direct activator MKK6 are rapidly activated in response to TGF-beta. SIGNOR-70607 SIGNOR-FapWNT FAP: Wnt GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 BTO:0000938 BTO:0000142 19303846 YES lperfetto GSK3β regulates β-catenin stability by phosphorylating serine and threonine residues (Ser33/37 and Thr41) important for targeting β-catenin for ubiquitin-dependent proteasomal degradation SIGNOR-227870 SIGNOR-FapWNT FAP: Wnt GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 11955436 YES lperfetto Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). SIGNOR-227897 SIGNOR-FapWNT FAP: Wnt GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 BTO:0000938 BTO:0000142 19303846 YES lperfetto GSK3β regulates β-catenin stability by phosphorylating serine and threonine residues (Ser33/37 and Thr41) important for targeting β-catenin for ubiquitin-dependent proteasomal degradation SIGNOR-227874 SIGNOR-FapWNT FAP: Wnt GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 11955436 YES lperfetto Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). SIGNOR-227901 SIGNOR-FapWNT FAP: Wnt GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 11955436 YES lperfetto Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). SIGNOR-227905 SIGNOR-FapWNT FAP: Wnt GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 BTO:0000938 BTO:0000142 19303846 YES lperfetto GSK3β regulates β-catenin stability by phosphorylating serine and threonine residues (Ser33/37 and Thr41) important for targeting β-catenin for ubiquitin-dependent proteasomal degradation SIGNOR-227878 SIGNOR-FapWNT FAP: Wnt GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000586 16293724 YES lperfetto Because phosphorylation of β-catenin by GSK-3β leads to its rapid ubiquitination and subsequent degradation in the proteosome, inactivation of GSK-3β is often a prerequisite for stimulating the accumulation, nuclear translocation, and functional activity of β-catenin SIGNOR-227893 SIGNOR-FapWNT FAP: Wnt TCF7L2 protein Q9NQB0 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates activity transcriptional regulation 20492721 NO FFerrentino These findings suggested that miR-210 could promote adipogenesis by repressing WNT signaling through targeting Tcf7l2. SIGNOR-253519 SIGNOR-FapWNT FAP: Wnt WNT10B protein O00744 UNIPROT FZD1 protein Q9UP38 UNIPROT up-regulates activity binding 9606 19008118 YES FFerrentino In mesenchymal precursor cells, Wnt10b (and Wnt10a) binding to frizzled (FZD1) SIGNOR-253511 SIGNOR-FapWNT FAP: Wnt WNT10B protein O00744 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131631 SIGNOR-FapWNT FAP: Wnt FZD4 protein Q9ULV1 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 27096005 YES areggio Through study of FZD4 and its associated ligand Norrin, we report that a minimum of three residues distal to the KTXXXW motif in the C-terminal tail of Frizzled-4 are essential for DVL recruitment and robust Lef/Tcf-dependent transcriptional activation in response to Norrin. SIGNOR-258955 SIGNOR-FapWNT FAP: Wnt FZD1 protein Q9UP38 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 22944199 YES amattioni When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp. SIGNOR-253512 SIGNOR-FapWNT FAP: Wnt FZD2 protein Q14332 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 23151663 YES areggio Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.  SIGNOR-258956 SIGNOR-FapWNT FAP: Wnt PPARG protein P37231 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0004300 16150867 NO lperfetto Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor SIGNOR-256229 SIGNOR-FapWNT FAP: Wnt CTNNB1 protein P35222 UNIPROT PPARG protein P37231 UNIPROT down-regulates activity binding 10090 BTO:0003346 16847334 YES Oncogenic beta-catenin resists proteasomal degradation by inhibiting PPARgamma activity, which requires its TCF/LEF binding domain SIGNOR-256072 SIGNOR-FapWNT FAP: Wnt CTNNB1 protein P35222 UNIPROT PPARG protein P37231 UNIPROT down-regulates 9606 BTO:0000222 10937998 NO fspada Wnt-10b, is a molecular switch that governs adipogenesis. Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma). SIGNOR-80592 SIGNOR-FapWNT FAP: Wnt CTNNB1 protein P35222 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT up-regulates activity binding 9606 20492721 YES FFerrentino Hypophosphorylation of β-catenin and translocation into the nucleus leads to binding with members of the lymphoid-enhancer-binding factor/T-cell-specific transcription factor (LEF/TCF) family and activation of WNT target genesAs a member of LEF/TCF family, transcription factor 7 like 2 (Tcf7l2, formerly called Tcf4) is an important transcription factor triggering the downstream responsive genes of WNT signaling SIGNOR-85757 SIGNOR-FapWNT FAP: Wnt WNT5A protein P41221 UNIPROT FZD2 protein Q14332 UNIPROT up-regulates activity binding 9606 19008118 YES FFerrentino Perhaps through Wnt5a acting via FZD2, might also inhibit adipocyte differentiation. SIGNOR-253520 SIGNOR-FapWNT FAP: Wnt WNT5A protein P41221 UNIPROT FZD4 protein Q9ULV1 UNIPROT up-regulates activity binding 9606 16602827 YES areggio We show that in addition to its inhibitory function, Wnt5a can also activate beta-catenin signaling in the presence of the appropriate Frizzled receptor, Frizzled 4. SIGNOR-258954 SIGNOR-FapWNT FAP: Wnt SOX6 protein P35712 UNIPROT MEST protein Q5EB52 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003298 26893351 NO We found that SOX6 regulates adipogenesis in vertebrate species by activating adipogenic regulators including PPARγ, C/EBPα and MEST. SIGNOR-255823 SIGNOR-FapWNT FAP: Wnt SOX6 protein P35712 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity binding 10090 BTO:0000011 26893351 YES SOX6 interacts with β-catenin in adipocytes, suggesting an inhibition of WNT/β-catenin signaling, thereby promoting adipogenesis. SIGNOR-256073 SIGNOR-FapWNT FAP: Wnt SOX6 protein P35712 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003298 26893351 NO We found that SOX6 regulates adipogenesis in vertebrate species by activating adipogenic regulators including PPARŒ≥, C/EBPŒ± and MEST SIGNOR-255822 SIGNOR-FapWNT FAP: Wnt DVL1 protein O14640 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 15735151 YES amattioni Activated DVL binds and inhibits the phosphorylation of beta-catenin by GSK3B, blocking beta-catenin degradation so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1. SIGNOR-134285 SIGNOR-FapWNT FAP: Wnt DVL1 protein O14640 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9606 20837657 YES lperfetto In canonical wnt signaling, dsh phosphorylation inhibits the apcaxingsk3 complex, leading to beta-catenin stabilization. SIGNOR-227911 SIGNOR-FapWNT FAP: Wnt MEST protein Q5EB52 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates transcriptional regulation 9606 24827625 NO areggio Our data demonstrate that Mest alleviated CCl4-induced collagen deposition in liver tissue and improved the condition of the liver in rats. Mest also significantly reduced the expression and distribution of β-catenin, α-SMA and Smad3 both in vivo and in vitro, in addition to the viability of HSCs in vitro. SIGNOR-258982 SIGNOR-FapWNT FAP: Wnt MEST protein Q5EB52 UNIPROT LRP6 protein O75581 UNIPROT down-regulates activity 9606 21375506 NO Mest/Peg1 inhibited maturation of LRP6 by controlling the glycosylation of LRP6. Knockdown of Mest/Peg1, which might enhance Wnt signalling, blocked adipogenic differentiation of 3T3-L1 cells SIGNOR-255826 SIGNOR-FGCC FAP: GCR-cAMP crosstalk budesonide chemical CHEBI:3207 ChEBI NR3C1 protein P04150 UNIPROT up-regulates activity chemical activation -1 9793625 YES Mometasone furoate (MF, CAS 83919-23-7, Sch 32088), budesonide (BUD, CAS 51372-29-3), fluticasone propionate (FP, CAS 80474-14-2), and triamcinolone acetonide (TA, CAS-76-25-5) are corticosteroids. All of the test compounds had a higher affinity for the recombinant glucocorticoid receptor than the reference glucocorticoid receptor ligand, dexamethasone (DEX, CAS 50-02-2). All compounds showed greater potency than dexamethasone in stimulating transcription of a synthetic target gene regulated by a glucocorticoid response element. SIGNOR-253053 SIGNOR-FGCC FAP: GCR-cAMP crosstalk AMPK complex SIGNOR-C15 SIGNOR CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser170 PSALNRTsSDSALHT 9606 21892142 YES lperfetto Collectively, these findings suggest ampk suppresses glucose production through two transcriptional effects:reduced expression of creb targets via crtc inactivation and reduced expression of foxo target genes via class iia hdac inactivation SIGNOR-216541 SIGNOR-FGCC FAP: GCR-cAMP crosstalk TSC22D3 protein Q99576 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000011 12671681 NO In this study, we showed that GILZ, which is transcriptionally induced by GCs, inhibits the transcription of the PPAR-γ2 gene and blocks adipocyte differentiation SIGNOR-253296 SIGNOR-FGCC FAP: GCR-cAMP crosstalk CRTC2 protein Q53ET0 UNIPROT TSC22D3 protein Q99576 UNIPROT up-regulates quantity transcriptional regulation 9606 26652733 YES CRTC2 knockdown attenuates glucocorticoid-responsive GILZ mRNA expression in HeLa cells SIGNOR-256109 SIGNOR-FGCC FAP: GCR-cAMP crosstalk CREB1 protein P16220 UNIPROT CEBPB protein P17676 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 14593102 NO lperfetto Expression of constitutively active CREB strongly activated C/EBPbeta promoter-reporter genes, induced expression of endogenous C/EBPbeta, and caused adipogenesis in the absence of the hormonal inducers normally required SIGNOR-250573 SIGNOR-FGCC FAP: GCR-cAMP crosstalk PPARG protein P37231 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0004300 16150867 NO lperfetto Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor SIGNOR-256229 SIGNOR-FGCC FAP: GCR-cAMP crosstalk PRKACA protein P17612 UNIPROT STK11 protein Q15831 UNIPROT up-regulates activity phosphorylation Ser428 SSKIRRLsACKQQ 10116 11297520 YES miannu Phosphorylation of the protein kinase mutated in Peutz-Jeghers cancer syndrome, LKB1/STK11, at Ser431 by p90(RSK) and cAMP-dependent protein kinase, but not its farnesylation at Cys(433), is essential for LKB1 to suppress cell growth. SIGNOR-250055 SIGNOR-FGCC FAP: GCR-cAMP crosstalk PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000669 15568017 YES gcesareni Using a combination of in vitro explant assays, mutant analysis and gene delivery into mouse embryos cultured ex vivo, we demonstrate that adenylyl cyclase signalling via PKA and its target transcription factor CREB are required for WNT-directed myogenic gene expression. SIGNOR-131307 SIGNOR-FGCC FAP: GCR-cAMP crosstalk STK11 protein Q15831 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates phosphorylation -1 14614828 YES lperfetto We demonstrated that lkb1 phosphorylates ampk on the activation loop threonine (thr172) within the catalytic subunit and activates ampk in vitro. Here, we have investigated whether lkb1 corresponds to the major ampkk activity present in cell extracts. Ampkk purified from rat liver corresponds to lkb1, and blocking lkb1 activity in cells abolishes ampk activation in response to different stimuli SIGNOR-217469 SIGNOR-FGCC FAP: GCR-cAMP crosstalk CEBPB protein P17676 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity transcriptional regulation 10090 16431920 YES fspada These data suggest that c/CEBP beta activates a single unified pathway of adipogenesis involving its stimulation of PPARgamma expression, which then activates C/EBP alpha expression by dislodging HDAC1 from the promoter for degradation in the proteasome SIGNOR-143952 SIGNOR-FGCC FAP: GCR-cAMP crosstalk CEBPB protein P17676 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0000011 25451943 NO gcesareni Adipogenesis is controlled by a transcriptional cascade composed of a large number of transcriptional factors, among which CCAAT/enhancer-binding protein (C/EBP) β plays an essential role. SIGNOR-238297 SIGNOR-FGCC FAP: GCR-cAMP crosstalk NR3C1 protein P04150 UNIPROT CEBPB protein P17676 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000746 27777311 NO We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα. SIGNOR-256117 SIGNOR-FGCC FAP: GCR-cAMP crosstalk NR3C1 protein P04150 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000746 27777311 NO We observed GR binding on or near Cebpβ, Cebpδ, Klf5, Klf9, Cebpα, and Pparγ gene loci at 4 h but not at 0 h of adipogenesis. Thus, at least one of the mechanisms by which GR promotes adipogenesis in culture is by directly activating the expression of multiple adipogenic TFs. SIGNOR-256120 SIGNOR-FGCC FAP: GCR-cAMP crosstalk NR3C1 protein P04150 UNIPROT TSC22D3 protein Q99576 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001372 9430225 NO In thymocytes and peripheral T cells, GILZ gene expression is induced by DEX SIGNOR-253295 SIGNOR-FI FAP: INSR PI3K complex SIGNOR-C156 SIGNOR PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 YES lperfetto Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478 SIGNOR-252712 SIGNOR-FI FAP: INSR PI3K complex SIGNOR-C156 SIGNOR PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 12040186 YES lperfetto The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. SIGNOR-252713 SIGNOR-FI FAP: INSR PI3K complex SIGNOR-C156 SIGNOR PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates quantity 9606 21798082 YES lperfetto Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate. (pip2). SIGNOR-252722 SIGNOR-FI FAP: INSR PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 BTO:0000150 19573809 NO lperfetto However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth SIGNOR-252703 SIGNOR-FI FAP: INSR PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 12167717 NO lperfetto PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473, SIGNOR-252715 SIGNOR-FI FAP: INSR AKT proteinfamily SIGNOR-PF24 SIGNOR GATA2 protein P23769 UNIPROT down-regulates activity phosphorylation Ser401 QTRNRKMsNKSKKSK 9606 BTO:0000876 15837948 YES PI-3K/Akt-dependent manner. lperfetto We show that insulin induces gata2 phosphorylation on serine 401 in a pi-3k/akt-dependent manner. Insulin-dependent phosphorylation of serine 401 impairs gata2 translocation to the nucleus and its dna binding activity SIGNOR-244271 SIGNOR-FI FAP: INSR AKT proteinfamily SIGNOR-PF24 SIGNOR INSIG2 protein Q9Y5U4 UNIPROT down-regulates activity 10090 BTO:0000759 21723501 NO MTORC1 activation is not sufficient to stimulate hepatic SREBP1c in the absence of Akt signaling, revealing the existence of an additional downstream pathway also required for this induction. We provide evidence that this mTORC1-independent pathway involves Akt-mediated suppression of Insig2a, a liver-specific transcript encoding the SREBP1c inhibitor INSIG2. SIGNOR-256212 SIGNOR-FI FAP: INSR AKT proteinfamily SIGNOR-PF24 SIGNOR FOXA2 protein Q9Y261 UNIPROT down-regulates activity phosphorylation Thr156 KTYRRSYtHAKPPYS 9606 14500912 YES Foxa-2 physically interacts with Akt, a key mediator of the phosphatidylinositol 3-kinase pathway and is phosphorylated at a single conserved site (T156) that is absent in Foxa-1 and Foxa-3 proteins. This Akt phosphorylation site in Foxa-2 is highly conserved from mammals to insects. Mutant Foxa-2T156A is resistant to Akt-mediated phosphorylation, nuclear exclusion, and transcriptional inactivation of Foxa-2-regulated gene expression. SIGNOR-254974 SIGNOR-FI FAP: INSR AKT proteinfamily SIGNOR-PF24 SIGNOR FOXA2 protein Q9Y261 UNIPROT down-regulates phosphorylation 9606 14500912 YES �Foxa-2 physically interacts with Akt, a key mediator of the phosphatidylinositol 3-kinase pathway and is phosphorylated at a single conserved site (T156) that is absent in Foxa-1 and Foxa-3 proteins. This Akt phosphorylation site in Foxa-2 is highly conserved from mammals to insects. Mutant Foxa-2T156A is resistant to Akt-mediated phosphorylation, nuclear exclusion, and transcriptional inactivation of Foxa-2-regulated gene expression. SIGNOR-254978 SIGNOR-FI FAP: INSR AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 21440011 YES lperfetto Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs SIGNOR-252348 SIGNOR-FI FAP: INSR AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser319 TFRPRTSsNASTISG 9606 11237865 YES lperfetto The transcription factor, forkhead in rhabdomyosarcoma (fkhr), is phosphorylated at three amino acid residues (thr-24, ser-256 and ser-319) by protein kinase b (pkb)alpha.Fkhr (forkhead in rhabdomyosarcoma), afx (all1 fused gene from chromosome x) and fkhrl1 (fkhr-like 1) are phosphorylated directly by pkb in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus SIGNOR-252349 SIGNOR-FI FAP: INSR AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 21798082 YES lperfetto Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b). SIGNOR-252352 SIGNOR-FI FAP: INSR AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 YES lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. These results indicate that phosphorylation by PKB/Akt negatively regulates FKHR1 by promoting export from the nucleus. SIGNOR-252346 SIGNOR-FI FAP: INSR AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 YES lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-252347 SIGNOR-FI FAP: INSR AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 10090 BTO:0002572 18423396 YES lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation SIGNOR-252350 SIGNOR-FI FAP: INSR AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates relocalization 10090 BTO:0002572 18423396 YES lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation SIGNOR-252351 SIGNOR-FI FAP: INSR PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 YES lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 SIGNOR-FI FAP: INSR PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9534 9637919 YES lperfetto In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation. SIGNOR-58313 SIGNOR-FI FAP: INSR PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation -1 9094314 YES gcesareni We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1) SIGNOR-243274 SIGNOR-FI FAP: INSR PIP3 smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity relocalization 9606 BTO:0001130 23633519 YES lperfetto Akt is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates pips) with phosphate groups at positions 3,4 and 3,4,5 on the inositol ring. SIGNOR-236490 SIGNOR-FI FAP: INSR PIP3 smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity relocalization 9606 23119004 YES lperfetto Binding of IGF to IGF-1R activates PI3K to generate PIP3 which in turn recruits and activates proteins that contain a pleckstrin homology ph) domain, including AKT and PDK1. SIGNOR-236509 SIGNOR-FI FAP: INSR SCAP protein Q12770 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates activity binding 10029 12242332 YES miannu Insig-2, a second protein of the endoplasmic reticulum that blocks the processing of sterol regulatory element-binding proteins (SREBPs) by binding to SCAP (SREBP cleavage-activating protein) in a sterol-regulated fashion, thus preventing it from escorting SREBPs to the Golgi. By blocking this movement, insig-2, like the previously described insig-1, prevents the proteolytic processing of SREBPs by Golgi enzymes, thereby blocking cholesterol synthesis. SIGNOR-256210 SIGNOR-FI FAP: INSR PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10090 12808134 YES lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1). SIGNOR-134477 SIGNOR-FI FAP: INSR PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 15718470 YES gcesareni Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. SIGNOR-243203 SIGNOR-FI FAP: INSR PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 YES lperfetto The activation of PKBbeta and PKBamma by PDK11 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma) SIGNOR-244480 SIGNOR-FI FAP: INSR PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10116 BTO:0000142 10226025 YES lperfetto Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown. SIGNOR-244421 SIGNOR-FI FAP: INSR PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15743829 YES lperfetto 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt), SIGNOR-244469 SIGNOR-FI FAP: INSR INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1190 DIYETDYyRKGGKGL -1 2449432 YES lperfetto We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151; SIGNOR-106518 SIGNOR-FI FAP: INSR INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1361 SYEEHIPyTHMNGGK -1 3166375 YES lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-233560 SIGNOR-FI FAP: INSR INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1011 DVFPCSVyVPDEWEV -1 3166375 YES lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-233564 SIGNOR-FI FAP: INSR INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1185 FGMTRDIyETDYYRK -1 2449432 YES lperfetto We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151; SIGNOR-106510 SIGNOR-FI FAP: INSR INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1189 RDIYETDyYRKGGKG -1 2449432 YES lperfetto We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151; SIGNOR-106514 SIGNOR-FI FAP: INSR INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr992 DGPLGPLyASSNPEY -1 3166375 YES lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-106522 SIGNOR-FI FAP: INSR INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr999 YASSNPEyLSASDVF -1 3166375 YES lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-106526 SIGNOR-FI FAP: INSR INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1355 SLGFKRSyEEHIPYT -1 3166375 YES lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-22577 SIGNOR-FI FAP: INSR INSR protein P06213 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation Tyr580 LRKTRDQyLMWLTQK 9534 BTO:0000298 8385099 YES The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor. SIGNOR-252691 SIGNOR-FI FAP: INSR INSR protein P06213 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation Tyr368 STKMHGDyTLTLRKG 9534 8385099 YES The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor. SIGNOR-252692 SIGNOR-FI FAP: INSR INSR protein P06213 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation Tyr607 NENTEDQySLVEDDE 9534 BTO:0000298 8385099 YES The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor. SIGNOR-252693 SIGNOR-FI FAP: INSR FOXO1 protein Q12778 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 16670091 NO lperfetto FOXO1 coexpression dose-dependently repressed transcription from either the PPARgamma 1 or PPARgamma2 promoter reporter by 65%, whereas insulin (100 nm, 20-24 h) either partially or completely reversed this effect. SIGNOR-218013 SIGNOR-FI FAP: INSR FOXO1 protein Q12778 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 18423396 NO fspada Akt1/Pkb-alpha was found to be the major regulator of phosphorylation and nuclear export of Foxo1, whose presence in the nucleus strongly attenuates adipocyte differentiation. SIGNOR-178281 SIGNOR-FI FAP: INSR FOXO1 protein Q12778 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 12530968 NO Constitutively active Foxo1 prevents the differentiation of preadipocytes, while dominant-negative Foxo1 restores adipocyte differentiation of fibroblasts from insulin receptor-deficient mice. SIGNOR-254973 SIGNOR-FI FAP: INSR FOXO1 protein Q12778 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 12530968 NO �The present data provide a direct link between insulin signaling through Irs _ PI 3-kinase _ Akt and adipogenesis through Foxo1 phosphorylation. Inhibition of Foxo1 via phosphorylation appears to be required during the clonal expansion phase, and our data show that unrestrained Foxo1 activity prevents terminal differentiation. SIGNOR-254977 SIGNOR-FI FAP: INSR FOXO1 protein Q12778 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 12530968 NO �The present data provide a direct link between insulin signaling through Irs _ PI 3-kinase _ Akt and adipogenesis through Foxo1 phosphorylation. Inhibition of Foxo1 via phosphorylation appears to be required during the clonal expansion phase, and our data show that unrestrained Foxo1 activity prevents terminal differentiation. SIGNOR-254981 SIGNOR-FI FAP: INSR INS protein P01308 UNIPROT INSR protein P06213 UNIPROT up-regulates activity binding 10029 16956584 YES lperfetto Insulin binds to the alpha subunit of the insulin receptor (IR) on the cell surface. SIGNOR-236748 SIGNOR-FI FAP: INSR INS protein P01308 UNIPROT INSR protein P06213 UNIPROT up-regulates activity binding 9606 2550426 YES lperfetto Our previous studies indicated that amino acid residues 240-250 in the cysteine-rich region of the human insulin receptor alpha-subunit constitute a site in which insulin binds. SIGNOR-23001 SIGNOR-FI FAP: INSR FOXA2 protein Q9Y261 UNIPROT DLK1 protein P80370 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 12865419 YES Taken together, these data suggest that Foxa-2 is a direct transcriptional activator of the Pref-1 gene. SIGNOR-254971 SIGNOR-FI FAP: INSR DLK1 protein P80370 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 9606 22640926 NO fspada We conclude that DLK1(PREF1) is well expressed in human ASC and acts as a negative regulator of adipogenesis. SIGNOR-197634 SIGNOR-FI FAP: INSR DLK1 protein P80370 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 8500166 NO This indicates that pref-1 functions as a negative regulator of adipocyte differentiation, possibly in a manner analogous to EGF-like proteins that govern cell fate decisions in invertebrates. SIGNOR-254980 SIGNOR-FI FAP: INSR PPARG protein P37231 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0004300 16150867 NO lperfetto Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor SIGNOR-256229 SIGNOR-FI FAP: INSR INSIG2 protein Q9Y5U4 UNIPROT SCAP protein Q12770 UNIPROT down-regulates activity binding 10029 BTO:0000246 12242332 YES insig-2, a second protein of the endoplasmic reticulum that blocks the processing of sterol regulatory element-binding proteins (SREBPs) by binding to SCAP (SREBP cleavage-activating protein) in a sterol-regulated fashion, thus preventing it from escorting SREBPs to the Golgi. SIGNOR-256209 SIGNOR-FI FAP: INSR GATA2 protein P23769 UNIPROT PPARG protein P37231 UNIPROT down-regulates activity 9606 20510530 YES fferrentino GATA2 interacts directly with PPARG and C/EBP a , which may deplete PPARG involved in the promotion of adipogenesis SIGNOR-132949 SIGNOR-FI FAP: INSR SREBF1 protein P36956 UNIPROT PPARG protein P37231 UNIPROT up-regulates activity 10090 9539737 NO gcesareni Finally, we demonstrate directly that cells expressing ADD1/SREBP1 produce and secrete lipid molecule(s) that bind directly to PPARgamma, displacing the binding of radioactive thiazolidinedione ligands SIGNOR-170607 SIGNOR-FibroARG Fibroblast: Arginine metabolism and collagen synthesis proline smallmolecule CHEBI:26271 ChEBI ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 25386178 NO apalma Ornithine, via the enzyme OAT, is also a precursor amino acid for the synthesis of proline, which itself is essential for the synthesis of collagen. SIGNOR-255550 SIGNOR-FibroARG Fibroblast: Arginine metabolism and collagen synthesis putrescine smallmolecule CHEBI:17148 ChEBI Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 14617280 NO apalma Cell proliferation is highly dependent on the synthesis of polyamines, which are derived from arginine metabolism SIGNOR-255551 SIGNOR-FibroARG Fibroblast: Arginine metabolism and collagen synthesis spermine smallmolecule CHEBI:15746 ChEBI Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 14617280 NO apalma Cell proliferation is highly dependent on the synthesis of polyamines, which are derived from arginine metabolism SIGNOR-255552 SIGNOR-FibroARG Fibroblast: Arginine metabolism and collagen synthesis spermidine smallmolecule CHEBI:16610 ChEBI Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 14617280 NO apalma Cell proliferation is highly dependent on the synthesis of polyamines, which are derived from arginine metabolism SIGNOR-255553 SIGNOR-FibroARG Fibroblast: Arginine metabolism and collagen synthesis ODC1 protein P11926 UNIPROT spermidine smallmolecule CHEBI:16610 ChEBI up-regulates quantity chemical modification 9606 14617280 YES miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) SIGNOR-256038 SIGNOR-FibroARG Fibroblast: Arginine metabolism and collagen synthesis ODC1 protein P11926 UNIPROT spermine smallmolecule CHEBI:15746 ChEBI up-regulates quantity chemical modification 9606 14617280 YES miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) SIGNOR-256035 SIGNOR-FibroARG Fibroblast: Arginine metabolism and collagen synthesis ODC1 protein P11926 UNIPROT spermine smallmolecule CHEBI:15746 ChEBI up-regulates quantity chemical modification 9606 14617280 YES miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) SIGNOR-256036 SIGNOR-FibroARG Fibroblast: Arginine metabolism and collagen synthesis ODC1 protein P11926 UNIPROT putrescine smallmolecule CHEBI:17148 ChEBI up-regulates quantity chemical modification 9606 14617280 YES miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) SIGNOR-256034 SIGNOR-FibroARG Fibroblast: Arginine metabolism and collagen synthesis ODC1 protein P11926 UNIPROT L-ornithine smallmolecule CHEBI:15729 ChEBI down-regulates quantity chemical modification 9606 14617280 YES miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) SIGNOR-256037 SIGNOR-FibroARG Fibroblast: Arginine metabolism and collagen synthesis OAT protein P04181 UNIPROT L-ornithine smallmolecule CHEBI:15729 ChEBI down-regulates quantity chemical modification 9606 14617280 YES miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) SIGNOR-256032 SIGNOR-FibroARG Fibroblast: Arginine metabolism and collagen synthesis OAT protein P04181 UNIPROT proline smallmolecule CHEBI:26271 ChEBI up-regulates quantity chemical modification 9606 14617280 YES miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) SIGNOR-256033 SIGNOR-FibroARG Fibroblast: Arginine metabolism and collagen synthesis ARG1 protein P05089 UNIPROT L-ornithine smallmolecule CHEBI:15729 ChEBI up-regulates quantity chemical modification 9606 14617280 YES miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) SIGNOR-255545 SIGNOR-FibroFN1TR Fibroblast: FN1 transcriptional regulation SNAIL/RELA/PARP1 complex SIGNOR-C198 SIGNOR FN1 protein P02751 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000452;BTO:0002625 22223884 NO alessandro Taken together, our results indicate that Snail1, p65NF-κB and PARP1 interact to activate the expression of fibronectin and other ECM genes involved in cell movement. This mechanism is functional not only in epithelial cells undergoing EMT but also in fibroblasts. SIGNOR-254529 SIGNOR-FibroFN1TR Fibroblast: FN1 transcriptional regulation RELA protein Q04206 UNIPROT SNAIL/RELA/PARP1 complex SIGNOR-C198 SIGNOR form complex binding 9606 BTO:0000452;BTO:0002625 22223884 YES alessandro Therefore, we conclude that the endogenous proteins PARP1, p65NF-κB and Snail1 form a ternary complex in the nuclei of cells that are actively expressing fibronectin SIGNOR-254527 SIGNOR-FibroFN1TR Fibroblast: FN1 transcriptional regulation PARP1 protein P09874 UNIPROT SNAIL/RELA/PARP1 complex SIGNOR-C198 SIGNOR form complex binding 9606 22223884 YES alessandro Therefore, we conclude that the endogenous proteins PARP1, p65NF-κB and Snail1 form a ternary complex in the nuclei of cells that are actively expressing fibronectin SIGNOR-254528 SIGNOR-FibroFN1TR Fibroblast: FN1 transcriptional regulation SNAI1 protein O95863 UNIPROT SNAIL/RELA/PARP1 complex SIGNOR-C198 SIGNOR form complex binding 9606 BTO:0000452;BTO:0002625 22223884 YES alessandro Therefore, we conclude that the endogenous proteins PARP1, p65NF-κB and Snail1 form a ternary complex in the nuclei of cells that are actively expressing fibronectin SIGNOR-254526 SIGNOR-FICA FAP: IL15 JAK3 protein P52333 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation 9606 30029643 YES Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated SIGNOR-256254 SIGNOR-FICA FAP: IL15 IL15 protein P40933 UNIPROT IL15RA protein Q13261 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 17709786 YES Interleukin-15 specificity and high affinity binding are conferred by the IL-5-specific but nonsignaling IL-15R alpha subunit, which is structurally similar (but not homologous) to the alpha receptor subunit of IL-2 SIGNOR-157415 SIGNOR-FICA FAP: IL15 PPARG protein P37231 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 16150867 NO lperfetto Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor SIGNOR-228622 SIGNOR-FICA FAP: IL15 TIMP3 protein P35625 UNIPROT MMP14 protein P50281 UNIPROT down-regulates activity binding 10090 BTO:0005300 28709001 YES FAP cilia regulated the expression of TIMP3, a secreted metalloproteinase inhibitor, that inhibited MMP14 to block adipogenesis. SIGNOR-255908 SIGNOR-FICA FAP: IL15 TYK2 protein P29597 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation 9606 30029643 YES Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated SIGNOR-256255 SIGNOR-FICA FAP: IL15 STAT3 protein P40763 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 30029643 NO Taken together, our data show IL-15 can enhance the collagen deposition in vivo after muscle damage and this process can be prevented by blocking Jak-STAT pathway. SIGNOR-256257 SIGNOR-FICA FAP: IL15 STAT3 protein P40763 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0003298 BTO:0001103 30029643 NO In summary, our results indicate IL-15 can stimulate the proliferation of FAPs through Jak-STAT pathway. SIGNOR-256256 SIGNOR-FICA FAP: IL15 IL15RA protein Q13261 UNIPROT TYK2 protein P29597 UNIPROT up-regulates 9606 30029643 YES Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated SIGNOR-256253 SIGNOR-FICA FAP: IL15 IL15RA protein Q13261 UNIPROT TIMP3 protein P35625 UNIPROT up-regulates 9606 30029643 NO areggio Since recent study demonstrated desert Hedgehog (DHH) signaling can repressed FAP-derived adipocyte differentiation through Timp3 [30], we tested the mRNA expression of DHH and Timp3 in injured muscle with injection of IL-15. As expected, mRNA levels of DHH and Timp3 were both upregulated (Fig. 2f). SIGNOR-256232 SIGNOR-FICA FAP: IL15 IL15RA protein Q13261 UNIPROT PPARG protein P37231 UNIPROT down-regulates activity 9606 30029643 NO areggio In addition, level of mRNAs encoding C/EBPa, PPARg and FABP4, the classic adipogenic markers, was significantly lower in samples administrated with IL-15 SIGNOR-256228 SIGNOR-FICA FAP: IL15 IL15RA protein Q13261 UNIPROT JAK3 protein P52333 UNIPROT up-regulates 9606 30029643 YES Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated SIGNOR-256226 SIGNOR-FICA FAP: IL15 MMP14 protein P50281 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 28709001 NO MMP14 Promotes Adipogenesis Downstream of or in Parallel to TIMP3 SIGNOR-255909 SIGNOR-FMAA FAP: miRNA and adipogensis miR-199a mirna URS0000759977_9606 RNAcentral RPS6 protein P62753 UNIPROT up-regulates activity 10090 21986534 YES This overexpression of miR-155 may suppress the expression of C/EBPβ and CREB by directly targeting their 3' untranslated regions (3' UTRs) SIGNOR-255936 SIGNOR-FMAA FAP: miRNA and adipogensis miR-23a mirna URS00001CC864_9606 RNAcentral ZNF423 protein Q2M1K9 UNIPROT down-regulates quantity post transcriptional regulation 9606 19800867 YES These results suggest that the anti-adipogenic effect of miR-27b in hMADS cells is due, at least in part, to suppression of PPARgamma. SIGNOR-255934 SIGNOR-FMAA FAP: miRNA and adipogensis miR-23b mirna URS0000283D0A_9606 RNAcentral GLS protein O94925 UNIPROT down-regulates quantity post transcriptional regulation 10090 21135128 YES MiR-130 reduces adipogenesis by repressing PPARγ biosynthesis and suggest that perturbations in this regulation is linked to human obesity. SIGNOR-255930 SIGNOR-FMAA FAP: miRNA and adipogensis miR-29b mirna URS0000150A7D_9606 RNAcentral DNMT3A protein Q9Y6K1 UNIPROT down-regulates quantity by repression post transcriptional regulation 9913 28255176 YES Target prediction analysis revealed that ZNF423 was a potential target of bta-miR-23a. Dual-luciferase reporter assay revealed that bta-miR-23a directly targeted the 3′-UTR of ZNF423. SIGNOR-255927 SIGNOR-FMAA FAP: miRNA and adipogensis TNF protein P01375 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity 9606 8530143 NO andrea cerquone perpetuini Data from our laboratory demonstrate that the TNF signal transduction pathway-mediating NF-kappa B activation involves two phospholipases, a phosphatidylcholine-specific phospholipase C (PC-PLC) and an endosomal acidic sphingomyelinase (aSMase). The aSMase activation by TNF is secondary to the generation of 1,2-diacylglycerol (DAG) produced by a TNF-responsive PC-PLC. SMase and its product ceramide induce degradation of the NF-kappa B inhibitor I kappa B as well as NF-kappa B activation. SIGNOR-255689 SIGNOR-FMAA FAP: miRNA and adipogensis PPARG protein P37231 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0004300 16150867 NO lperfetto Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor SIGNOR-256229 SIGNOR-FMAA FAP: miRNA and adipogensis ZNF423 protein Q2M1K9 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates activity 10090 BTO:0000011 20200519 NO Ectopic expression of Zfp423 in non-adipogenic NIH 3T3 fibroblasts robustly activates expression of Pparg in undifferentiated cells and permits cells to undergo adipocyte differentiation under permissive conditions. Short hairpin RNA (shRNA)-mediated reduction of Zfp423 expression in 3T3-L1 cells blunts preadipocyte Pparg expression and diminishes the ability of these cells to differentiate. SIGNOR-255928 SIGNOR-FMAA FAP: miRNA and adipogensis SPI1 protein P17947 UNIPROT miR-34 mirna URS000033F823_9606 RNAcentral up-regulates quantity by expression transcriptional regulation 10090 21986534 NO We revealed that TNFα treatment results in the up-regulation of miR-155 through the NFκB pathway in 3T3-L1 cells. SIGNOR-255935 SIGNOR-FMAA FAP: miRNA and adipogensis CEBPB protein P17676 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity transcriptional regulation 10090 16431920 YES fspada These data suggest that c/CEBP beta activates a single unified pathway of adipogenesis involving its stimulation of PPARgamma expression, which then activates C/EBP alpha expression by dislodging HDAC1 from the promoter for degradation in the proteasome SIGNOR-143952 SIGNOR-FMAA FAP: miRNA and adipogensis CEBPB protein P17676 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity transcriptional regulation 10090 7557387 YES Andrea Cerquone Perpetuini  Induction of C/EBP beta DNA-binding activity in NIH-3T3 beta 2 cells exposed to dexamethasone in the presence of insulin and fetal bovine serum activates the expression of an adipocyte-specific nuclear hormone receptor, PPAR gamma, that stimulates the conversion of these fibroblasts into committed preadipocytes SIGNOR-255730 SIGNOR-MacroIFNG Macrophage: IFN gamma IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR STAT1 protein P42224 UNIPROT up-regulates activity binding 9606 23898330 YES lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249494 SIGNOR-MacroIFNG Macrophage: IFN gamma IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR JAK2 protein O60674 UNIPROT up-regulates activity binding 9606 BTO:0000801 23898330 YES lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249506 SIGNOR-MacroIFNG Macrophage: IFN gamma NOS2 protein P35228 UNIPROT nitric oxide smallmolecule CHEBI:16480 ChEBI up-regulates 9606 7537672 NO apalma Activation with lipopolysaccharide induces macrophages to produce the enzymes arginase and nitric oxide (NO) synthase. Both enzymes use as a substrate the ammino acid L-arginine, which can be either hydrolyzed by arginase to urea and ornithine or oxidized by NO synthase to NO and citrulline SIGNOR-255381 SIGNOR-MacroIFNG Macrophage: IFN gamma NOS2 protein P35228 UNIPROT L-citrulline smallmolecule CID:9750 ChEBI up-regulates 9606 7537672 NO apalma Activation with lipopolysaccharide induces macrophages to produce the enzymes arginase and nitric oxide (NO) synthase. Both enzymes use as a substrate the ammino acid L-arginine, which can be either hydrolyzed by arginase to urea and ornithine or oxidized by NO synthase to NO and citrulline SIGNOR-255382 SIGNOR-MacroIFNG Macrophage: IFN gamma IFNG protein P01579 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR up-regulates activity binding 9606 BTO:0000801 23898330 YES lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249487 SIGNOR-MacroIFNG Macrophage: IFN gamma SOCS1 protein O15524 UNIPROT STAT1 protein P42224 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16628196 NO miannu SOCS1, which is another inducible gene, not only blocks STAT1 activation but also inhibits STAT1-dependent TLR3, IRF-7, and MIP-1α. SIGNOR-255229 SIGNOR-MacroIFNG Macrophage: IFN gamma JAK2 protein O60674 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation 7888666 YES apalma We found that IL-5 induced two GAS-binding proteins in the nuclear extract from eosinophils. One of them was identified as STAT1 (p91). SIGNOR-255071 SIGNOR-MacroIFNG Macrophage: IFN gamma JAK2 protein O60674 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000567 15322115 YES lperfetto Phosphorylation at tyr701 by the janus family of tyrosine kinases (jak) leads to stat1 dimerization via its src homology 2 domains, exposure of a dimer-specific nuclear localization signal, and subsequent nuclear translocation. SIGNOR-235709 SIGNOR-MacroIFNG Macrophage: IFN gamma JAK2 protein O60674 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000801 23898330 YES lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249493 SIGNOR-MacroIFNG Macrophage: IFN gamma STAT6 protein P42226 UNIPROT STAT1 protein P42224 UNIPROT down-regulates activity binding 9606 BTO:0000801 10982806 YES lperfetto STAT6 mediates suppression of STAT1 and NF-kB-dependent transcription by distinct mechanisms. Both processes are dependent upon the STAT6 transactivation domain and may involve sequestration of necessary but different transcriptional coactivator proteins. These two suppressive mechanisms are controlled differentially by the nature of the STAT6 DNA-binding site SIGNOR-249552 SIGNOR-MacroIFNG Macrophage: IFN gamma STAT1 protein P42224 UNIPROT CIITA protein P33076 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 19029990 NO lperfetto STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others. SIGNOR-249498 SIGNOR-MacroIFNG Macrophage: IFN gamma STAT1 protein P42224 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity binding 9606 19041276 YES lperfetto Each STAT1 monomer becomes tyrosine phosphorylated at tyrosine 701 by the JAKs, dissociates from the receptor to form a STAT1-STAT1 homodimer which translocates to the nucleus SIGNOR-249495 SIGNOR-MacroIFNG Macrophage: IFN gamma STAT1 protein P42224 UNIPROT SOCS1 protein O15524 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19482358 NO miannu Socs1 expression is induced in the human keratinocytes HaCaT cell line through sequential activation of STAT1 and IRF-1 SIGNOR-226484 SIGNOR-MacroIFNG Macrophage: IFN gamma STAT1 protein P42224 UNIPROT NOS2 protein P35228 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19029990 YES lperfetto STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others. SIGNOR-249497 SIGNOR-MacroIFNG Macrophage: IFN gamma STAT1 protein P42224 UNIPROT MMP13 protein P45452 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000249 17179173 NO miannu IFNgamma, through its receptor, activates STAT1, which binds with CBP/p300 coactivator, sequesters it from the cell system, and thus inhibits transcriptional induction of the MMP13 gene in chondrocytes. SIGNOR-255235 SIGNOR-MacroIFNG Macrophage: IFN gamma STAT1 protein P42224 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 9606 19029990 NO lperfetto STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others. SIGNOR-249496 SIGNOR-MacroIFNG Macrophage: IFN gamma JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000567 11823427 YES lperfetto The central event in cytokine_dependent transcriptional regulation is phosphorylation of STATs on a single tyrosine residue at their C_terminus (Darnell, 1997b). The reaction is catalyzed by cytokine receptor_associated tyrosine kinases of the Janus type (Jak) at the cell membrane and triggers the homo_ and heterodimerization of STAT molecules via reciprocal phosphotyrosine“SH2 domain interactions SIGNOR-236373 SIGNOR-MacroIFNG Macrophage: IFN gamma JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 9020188 YES lperfetto The stat1 and stat2 proteins are present in the cytoplasm of untreated cells;upon stimulation with ifn-g they become rapidly activated by tyrosine phosphorylation at a single site catalyzed by receptor associated jak (janus) kinases. SIGNOR-236239 SIGNOR-MacroIFNG Macrophage: IFN gamma JAK1 protein P23458 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000801 19041276 YES lperfetto The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process. SIGNOR-249492 SIGNOR-MacroIL1 Macrophage: IL1 beta NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCL2 protein P13500 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000801 20086235 NO Both NF-κBs bind to a conserved DNA motif (80) that is found in numerous IL-1–responsive genes, in particular the ones encoding IκBα (81), IL-6 (82), IL-8 (18, 83,84), monocyte chemoattractant protein 1 (MCP1) (28), and cyclooxygenase 2 (COX2) SIGNOR-254509 SIGNOR-MacroIL1 Macrophage: IL1 beta NfKb-p65/p50 complex SIGNOR-C13 SIGNOR IL6 protein P05231 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000801 20086235 NO Both NF-κBs bind to a conserved DNA motif (80) that is found in numerous IL-1–responsive genes, in particular the ones encoding IκBα (81), IL-6 (82), IL-8 (18, 83,84), monocyte chemoattractant protein 1 (MCP1) (28), and cyclooxygenase 2 (COX2) SIGNOR-254511 SIGNOR-MacroIL1 Macrophage: IL1 beta NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 20457564 NO gcesareni The nuclear factor NF-kappaB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-kappaB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules. SIGNOR-245039 SIGNOR-MacroIL1 Macrophage: IL1 beta AP1 complex SIGNOR-C154 SIGNOR IL6 protein P05231 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000801 20086235 NO JNK phosphorylates proteins that are part of AP-1, in particular c-Jun and activating transcription factor 2 (ATF-2). With dominant-negative mutants, antisense RNA, inhibitors, and genetic ablation, it has been shown that JNK and c-Jun play a major role in IL-1–induced expression of genes encoding IL-6 and IL-8 and other IL-1–responsive genes SIGNOR-254513 SIGNOR-MacroIL1 Macrophage: IL1 beta JNK proteinfamily SIGNOR-PF15 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 15916964 YES lperfetto Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities SIGNOR-137627 SIGNOR-MacroIL1 Macrophage: IL1 beta JNK proteinfamily SIGNOR-PF15 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 15916964 YES lperfetto Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities SIGNOR-137631 SIGNOR-MacroIL1 Macrophage: IL1 beta JNK proteinfamily SIGNOR-PF15 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 24315690 YES miannu In addition to the possible regulation of the transcription factor c-Jun by phosphorylation via the c-Jun N-terminal kinase (JNK) or the kinases ERK1, ERK2 and GSK3β, further signaling pathways lead to an up-regulation of c-Jun protein and thus AP-1 activity SIGNOR-253340 SIGNOR-MacroIL1 Macrophage: IL1 beta IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 9346241 YES lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-216385 SIGNOR-MacroIL1 Macrophage: IL1 beta IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 9346241 YES lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-216389 SIGNOR-MacroIL1 Macrophage: IL1 beta IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation 9606 21232017 YES lperfetto Tak1 become activated and then phosphorilates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation SIGNOR-216396 SIGNOR-MacroIL1 Macrophage: IL1 beta IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 BTO:0000567 9346241 YES lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-209773 SIGNOR-MacroIL1 Macrophage: IL1 beta IKK-complex complex SIGNOR-C14 SIGNOR IKK-complex complex SIGNOR-C14 SIGNOR down-regulates phosphorylation 9606 10195894 YES lperfetto Once activated, ikkbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased ikk activity and may prevent prolonged activation of the inflammatory response SIGNOR-216373 SIGNOR-MacroIL1 Macrophage: IL1 beta IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 BTO:0000007 19609947 YES lperfetto Our data suggest that the stimulation of nfkb by akt is dependent on the phosphorylation of p65 at s534, mediated by ikk (ikb kinase) alfa and beta. SIGNOR-216365 SIGNOR-MacroIL1 Macrophage: IL1 beta IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 15489227 YES lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. SIGNOR-216341 SIGNOR-MacroIL1 Macrophage: IL1 beta TRAF6 protein Q9Y4K3 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity ubiquitination Lys34 NFEEIDYkEIEVEEV 9606 18758450 YES lperfetto Intriguingly, TGF-beta-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6. SIGNOR-236071 SIGNOR-MacroIL1 Macrophage: IL1 beta RELA protein Q04206 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000801 27337441 YES lperfetto Recent reports show that in mice the microbiome, comprising commensal microorganisms that colonize body surfaces, promotes a partial and low-grade M1-like phenotype in macrophages throughout the body, including those in lymphoid organs (119, 120). This M1-like priming of macrophages induces chromatin remodeling with increased H3K4me3 marks at Ifnb, Il6, and Tnf promoters, which is associated with increased binding of NF-κB p65, IRF3, and Pol II upon cell stimulation SIGNOR-251737 SIGNOR-MacroIL1 Macrophage: IL1 beta MYD88 protein Q99836 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity binding 10090 BTO:0003432 10217414 YES lperfetto Interleukin-1 (il-1) stimulates the association of the il-1 receptor-associated protein kinase (irak) with the heterodimer of il-iri and il-iracp via the adapter protein myd88. Myd88 binds to both irak (il-1 receptor-associated kinase) and the heterocomplex (the signaling complex) of the two receptor chains and thereby mediates the association of irak with the receptor. SIGNOR-67143 SIGNOR-MacroIL1 Macrophage: IL1 beta IL1B protein P01584 UNIPROT IL1RAP protein Q9NPH3 UNIPROT up-regulates binding 9606 9820540 YES gcesareni The recently described il-1r accessory protein (il-1r acp) interacts with il-1beta and the il-1 type-ir (il-1ri). SIGNOR-61744 SIGNOR-MacroIL1 Macrophage: IL1 beta IL1B protein P01584 UNIPROT IL1R1 protein P14778 UNIPROT up-regulates binding 9606 BTO:0001253 9625767 YES gcesareni Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab). SIGNOR-58122 SIGNOR-MacroIL1 Macrophage: IL1 beta IL1B protein P01584 UNIPROT IL1R1 protein P14778 UNIPROT up-regulates activity binding 9606 BTO:0000801 24166242 YES lperfetto Pro-IL-1beta, mIL-1beta and mIL-beta all bind to IL-1RI, which recruits the IL-1 receptor accessory protein (IL-1RAcP) as a co-receptor. SIGNOR-249511 SIGNOR-MacroIL1 Macrophage: IL1 beta IL1B protein P01584 UNIPROT IL1R2 protein P27930 UNIPROT down-regulates binding 9606 BTO:0000876 8332913 YES gcesareni Interleukin-1 (il-1) interacts with cells through two types of binding molecules, il-1 type i receptor (il-1r i) and il-1r ii. Il-1r ii inhibits il-1 activity by acting as a decoy target for il-1 SIGNOR-38302 SIGNOR-MacroIL1 Macrophage: IL1 beta IL1R1 protein P14778 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity 9606 BTO:0000007 14625308 NO lperfetto Formation of the signaling il-1 receptor complex results in the activation and hyperphosphorylation of irak-1. SIGNOR-119208 SIGNOR-MacroIL1 Macrophage: IL1 beta IL1R1 protein P14778 UNIPROT IL1RAP protein Q9NPH3 UNIPROT up-regulates activity binding 9606 BTO:0000007 10854325 YES lperfetto Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1β treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip–IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs) SIGNOR-251981 SIGNOR-MacroIL1 Macrophage: IL1 beta IL1R1 protein P14778 UNIPROT MYD88 protein Q99836 UNIPROT up-regulates activity binding 9606 BTO:0003432 10217414 YES lperfetto Interleukin-1 (il-1) stimulates the association of the il-1 receptor-associated protein kinase (irak) with the heterodimer of il-iri and il-iracp via the adapter protein myd88. SIGNOR-67140 SIGNOR-MacroIL1 Macrophage: IL1 beta IL1RAP protein Q9NPH3 UNIPROT IL1R1 protein P14778 UNIPROT up-regulates binding 9606 12530978 YES gcesareni Here we report that the soluble form of the il-1 receptor accessory protein (acp) increases the affinity of binding of human il-1alpha and il-1beta to the soluble human type ii il-1 receptor by approximately 100-fold, SIGNOR-97396 SIGNOR-MacroIL1 Macrophage: IL1 beta MAP3K7 protein O43318 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates activity phosphorylation 9606 21232017 YES lperfetto Tak1 become activated and then phosphorilates and activates ikk2 whic in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. SIGNOR-209759 SIGNOR-MacroIL1 Macrophage: IL1 beta IRAK1 protein P51617 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0000007 8837778 YES lperfetto Il-1 treatment of 293 cells induces the association of traf6 with irak. SIGNOR-44234 SIGNOR-MacroIL1 Macrophage: IL1 beta IRAK1 protein P51617 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 12242293 YES lperfetto We now find that the phosphorylated IRAK in turn recruits TRAF6 to the receptor complex (complex I), which differs from the previous concept that IRAK interacts with TRAF6 after it leaves the receptor. IRAK then brings TRAF6 to TAK1 SIGNOR-92994 SIGNOR-MacroIL1 Macrophage: IL1 beta IRF3 protein Q14653 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000801 27337441 YES lperfetto Recent reports show that in mice the microbiome, comprising commensal microorganisms that colonize body surfaces, promotes a partial and low-grade M1-like phenotype in macrophages throughout the body, including those in lymphoid organs (119, 120). This M1-like priming of macrophages induces chromatin remodeling with increased H3K4me3 marks at Ifnb, Il6, and Tnf promoters, which is associated with increased binding of NF-κB p65, IRF3, and Pol II upon cell stimulation SIGNOR-251721 SIGNOR-MacroIL1 Macrophage: IL1 beta TP53 protein P04637 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 24737129 NO simone vumbaca We have identified a novel role for p53 that is specific to the regulation of several pro-inflammatory genes in human macrophages, including IL-6, IL-8 and CXCL1. Importantly, NF-κB co-activation is essential for this regulation SIGNOR-255969 SIGNOR-MacroIL1 Macrophage: IL1 beta IL1A protein P01583 UNIPROT IL1R1 protein P14778 UNIPROT up-regulates activity binding 9606 BTO:0000876 7964161 YES lperfetto Interleukin-1 receptor (il-1r) is a cytokine receptor which binds interleukin 1. SIGNOR-35077 SIGNOR-MacroIL1 Macrophage: IL1 beta IL1A protein P01583 UNIPROT IL1R1 protein P14778 UNIPROT up-regulates activity binding 9606 BTO:0001573 9565970 YES lperfetto Il-1ri is responsible for il-1 signaling SIGNOR-56718 SIGNOR-MacroIL1 Macrophage: IL1 beta NFKBIA protein P25963 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 1340770 YES lperfetto Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b SIGNOR-217394 SIGNOR-MacroIL1 Macrophage: IL1 beta NFKBIA protein P25963 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 9914500 YES lperfetto In nonstimulated cells, nf-kappab is present in the cytosol where it is complexed to its inhibitor ikappab however, we found that only one of the activities, namely the ikk1/2 complex, exists as a pre-assembled kinase-substrate complex in which the ikks are directly or indirectly associated with several nf-kappab-related and ikappab-related proteins: rela, relb, crel, p100, p105, ikappa balpha, ikappa bbeta and ikappa bepsilon. SIGNOR-64092 SIGNOR-MacroIL10 Macrophage: IL10 Phagocytosis phenotype SIGNOR-PH97 SIGNOR IL1B protein P01584 UNIPROT down-regulates quantity BTO:0000801 22933625 NO apalma Furthermore, phagocytosis of apoptotic neutrophils by M1 macrophages increased production of the Th2 cytokine TGFβ by the macrophages, while reducing expression of the Th1 cytokines IL-1β and TNF-α, reflecting a shift toward an M2 phenotype SIGNOR-255445 SIGNOR-MacroIL10 Macrophage: IL10 Phagocytosis phenotype SIGNOR-PH97 SIGNOR TGFB1 protein P01137 UNIPROT up-regulates quantity BTO:0000801 22933625 NO apalma Furthermore, phagocytosis of apoptotic neutrophils by M1 macrophages increased production of the Th2 cytokine TGFβ by the macrophages, while reducing expression of the Th1 cytokines IL-1β and TNF-α, reflecting a shift toward an M2 phenotype SIGNOR-255444 SIGNOR-MacroIL10 Macrophage: IL10 Phagocytosis phenotype SIGNOR-PH97 SIGNOR TNF protein P01375 UNIPROT down-regulates quantity BTO:0000801 22933625 NO apalma Furthermore, phagocytosis of apoptotic neutrophils by M1 macrophages increased production of the Th2 cytokine TGFβ by the macrophages, while reducing expression of the Th1 cytokines IL-1β and TNF-α, reflecting a shift toward an M2 phenotype SIGNOR-255446 SIGNOR-MacroIL10 Macrophage: IL10 M2_polarization phenotype SIGNOR-PH55 SIGNOR IL10 protein P22301 UNIPROT up-regulates quantity by expression 22933625 NO apalma P38 activation contributes to the macrophage phenotype switch in injured muscle, which could elevate production of IL-10 (63), creating positive feedback for the phenotype switch SIGNOR-255448 SIGNOR-MacroIL10 Macrophage: IL10 JAK2 protein O60674 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000599 9575217 YES lperfetto Activation of wild type stat3: il-6 treatment causes stat3 recruitment to receptor tyrosine phosphopeptides (gp130) where it is phosphorylated on tyrosine 705 (y) by jak kinase SIGNOR-236463 SIGNOR-MacroIL10 Macrophage: IL10 JAK2 protein O60674 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000599 9575217 YES lperfetto Inactive cytoplasmic STATs are recruited to the activated receptor by docking of the STAT SH2 domain to selected receptor tyrosine phosphopeptides, where they are in turn phosphorylated on a single tyrosine by Jak kinases. Has been identified tyrosine 705 of Stat3 as the likely site of phosphorylation by Jak kinases during signal transduction. SIGNOR-238638 SIGNOR-MacroIL10 Macrophage: IL10 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr637 KFGSLDTyLKKNKNC 9606 BTO:0000007 19364823 YES 16705160:The effect of Ser523 on Jak2 function was independent of Tyr570-mediated inhibition. lperfetto Analysis of in vitro autophosphorylated jak2while cytokine receptor stimulation mediates the phosphorylation of both tyr317 and tyr637, these residues oppositely regulate jak2-dependent signaling: the mutation of tyr317 enhances jak2 function, suggesting a role for the phosphorylation of tyr317 in the inhibition of jak2. Conversely, mutation of tyr637 reduces jak2 signaling, suggesting a role for the phosphorylation of this residue in the activation of jak2. SIGNOR-235885 SIGNOR-MacroIL10 Macrophage: IL10 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1007 VLPQDKEyYKVKEPG -1 9111318 YES Multiple autophosphorylation sites on Jak2, including Y1007 and Y1008. Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop. SIGNOR-251357 SIGNOR-MacroIL10 Macrophage: IL10 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr221 IRAKIQDyHILTRKR 9606 BTO:0000007 15143187 YES JAK2 is autophosphorylated on tyrosines 221 and 1007. tyrosines 221 and 570 in JAK2 may serve as regulatory sites in JAK2, with phosphorylation of tyrosine 221 increasing kinase activity and phosphorylation of tyrosine 570 decreasing kinase activity SIGNOR-251356 SIGNOR-MacroIL10 Macrophage: IL10 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT unknown phosphorylation Tyr1007 VLPQDKEyYKVKEPG -1 9111318 YES Within the Jak2 kinase domain, there is a region that has considerable sequence homology to the regulatory region of the insulin receptor and contains two tyrosines, Y1007 and Y1008, that are potential regulatory sites. Y1007 and Y1008 are sites of trans- or autophosphorylation in vivo and in in vitro kinase reactions. Mutation of Y1007, or both Y1007 and Y1008, to phenylalanine essentially eliminated kinase activity, whereas mutation of Y1008 to phenylalanine had no detectable effect on kinase activity SIGNOR-251358 SIGNOR-MacroIL10 Macrophage: IL10 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity phosphorylation Tyr570 VRREVGDyGQLHETE 9606 BTO:0000007 15143187 YES JAK2 is autophosphorylated on tyrosines 221 and 1007. tyrosines 221 and 570 in JAK2 may serve as regulatory sites in JAK2, with phosphorylation of tyrosine 221 increasing kinase activity and phosphorylation of tyrosine 570 decreasing kinase activity SIGNOR-251359 SIGNOR-MacroIL10 Macrophage: IL10 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr201 DQTPLAIyNSISYKT 9534 BTO:0000298 17027227 YES Site of Jak2 tyrosine autophosphorylation; namely, tyrosine 201. Jak2 tyrosine residue 201 was the principal mediator of SHP-2 binding as conversion of this tyrosine residue to phenylalanine abolished this interaction SIGNOR-251360 SIGNOR-MacroIL10 Macrophage: IL10 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr972 EYLGTKRyIHRDLAT 9606 BTO:0000007 20304997 YES lperfetto Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity SIGNOR-236294 SIGNOR-MacroIL10 Macrophage: IL10 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr813 NSLFTPDyELLTEND 9606 BTO:0000007 15121872 YES 16705160:The effect of Ser523 on Jak2 function was independent of Tyr570-mediated inhibition. lperfetto Tyrosine 813 is a site of jak2 autophosphorylation critical for activation of jak2 by sh2-b betawe show that phosphorylation of tyrosine 813 is required for the sh2 domain-containing adapter protein sh2-b beta to bind jak2 and to enhance the activity of jak2 and stat5b. SIGNOR-235910 SIGNOR-MacroIL10 Macrophage: IL10 IL10 protein P22301 UNIPROT IL10RA protein Q13651 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0000776 10347215 YES milica Functionally active il-10 receptors are composed of two distinct subunits. The il-10 receptor ? Chain is a 110-kda polypeptide that plays the dominant role in mediating high affinity ligand binding and signal transduction. The il-10 receptor ? Subunit (also known as crf2_4) is predicted to be a 40-kda polypeptide that is largely required only for signaling SIGNOR-67964 SIGNOR-MacroIL10 Macrophage: IL10 IL10 protein P22301 UNIPROT IL10RA protein Q13651 UNIPROT up-regulates activity binding 9606 BTO:0000801 26260587 YES lperfetto IL10 is a classic anti-inflammatory cytokine and its molecular signalling pathway has been well characterized in macrophages and T lymphocytes. Secreted IL10 cytokine binds to the IL10 receptor 1 (IL10R1) on membrane surfaces, and IL10R1 dimerizes with IL10R2 to exert its downstream effects. SIGNOR-249544 SIGNOR-MacroIL10 Macrophage: IL10 IRF5 protein Q13568 UNIPROT IL10 protein P22301 UNIPROT down-regulates transcriptional regulation 9606 BTO:0000801 21240265 NO The role of IRF5 in inhibiting the transcription of the gene encoding IL-10 that we have identified here is important given its well- documented immunosuppressive activity. SIGNOR-254514 SIGNOR-MacroIL10 Macrophage: IL10 FLI1 protein Q01543 UNIPROT IL10 protein P22301 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000801 20879862 NO In terms of cytokine expression, increased FLI-1 levels specifically enhanced IL-10 expression SIGNOR-254516 SIGNOR-MacroIL10 Macrophage: IL10 JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 9606 26260587 YES IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes. SIGNOR-253590 SIGNOR-MacroIL10 Macrophage: IL10 IL10RA protein Q13651 UNIPROT JAK1 protein P23458 UNIPROT up-regulates activity 9606 BTO:0000801 26260587 YES IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes. SIGNOR-253589 SIGNOR-MacroIL10 Macrophage: IL10 IL10RA protein Q13651 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 26260587 YES lperfetto IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes. SIGNOR-249545 SIGNOR-MacroIL10 Macrophage: IL10 IL10RA protein Q13651 UNIPROT Phagocytosis phenotype SIGNOR-PH97 SIGNOR up-regulates 19837374 NO apalma Treatment of monocytes with IL-10 as compared to IL-15 resulted in a two-fold greater level of phagocytosis and binding of latex beads. In summary, IL-10, in comparison to IL-15, induces greater macrophage endocytic function SIGNOR-255442 SIGNOR-MacroIL10 Macrophage: IL10 IL10RA protein Q13651 UNIPROT Phagocytosis phenotype SIGNOR-PH97 SIGNOR up-regulates 22933625 NO apalma Recent findings have shown that IL-10 stimulation of macrophages isolated from skeletal muscles increases the phagocytic activity of macrophages SIGNOR-255443 SIGNOR-MacroIL10 Macrophage: IL10 STAT3 protein P40763 UNIPROT IL10 protein P22301 UNIPROT up-regulates transcriptional regulation 9606 28713870 NO svumbaca These data argue that, in TH2 cells, STAT3 is required for T cell IL-10 production, which in turn reinforces its own expression SIGNOR-256234 SIGNOR-MacroIL10 Macrophage: IL10 STAT3 protein P40763 UNIPROT IL10 protein P22301 UNIPROT up-regulates transcriptional regulation 9606 22378047 NO IL-10 activates STAT3-mediated expression of genes (Il10, Tgfb1, Mrc1) associated with an M2-like phenotype SIGNOR-254515 SIGNOR-MacroIL10 Macrophage: IL10 STAT3 protein P40763 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000801 22378047 NO IL-10 activates STAT3-mediated expression of genes (Il10, Tgfb1, Mrc1) associated with an M2-like phenotype SIGNOR-254517 SIGNOR-MacroIL10 Macrophage: IL10 STAT3 protein P40763 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 10347215 NO lperfetto The data presented this far show that the JAK-STAT signaling pathway and specifically Stat3 and Jak1 are required for induction of IL-10-dependent anti-inflammatory and developmental responses in macrophages. SIGNOR-249547 SIGNOR-MacroIL10 Macrophage: IL10 MAPK14 protein Q16539 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 22933625 NO apalma The IL-10-mediated shift in macrophage phenotype in injured muscle may be amplified by activation of mitogen-activated protein kinase (MAPK), especially p38 MAPK, through signaling that is antagonized by MAPK phosphatase-1 (MKP-1). SIGNOR-255447 SIGNOR-MacroIL1BTR Macrophage: IL1 beta transcriptional regulation A9/b1 integrin complex SIGNOR-C166 SIGNOR IL1B protein P01584 UNIPROT up-regulates quantity by expression 9606 24241034 NO lperfetto Importantly, autocrine and paracrine interactions of α9β1 integrin and tenascin-C induced the expression of MMPs and IL-6 in synovial fibroblasts, as well as TNF-α and IL-1β in synovial macrophages. SIGNOR-253314 SIGNOR-MacroIL1BTR Macrophage: IL1 beta transcriptional regulation TNC protein P24821 UNIPROT A9/b1 integrin complex SIGNOR-C166 SIGNOR up-regulates activity binding 9606 BTO:0000801;BTO:0001336 24241034 YES lperfetto Synovial fibroblasts and macrophages derived from arthritic joints spontaneously secreted tenascin-C and osteopontin. Synovial fibroblasts and macrophages obtained from patients with RA expressed α9β1 integrins, a common receptor for osteopontin and tenascin-C. SIGNOR-253312 SIGNOR-MacroIL1BTR Macrophage: IL1 beta transcriptional regulation RELA protein Q04206 UNIPROT IL1B protein P01584 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20975042 YES svumbaca In addition, we show that the transcription of IL1B depends on a positively acting p65/c-Rel/ikbb complex SIGNOR-256237 SIGNOR-MacroIL1BTR Macrophage: IL1 beta transcriptional regulation HIF1A protein Q16665 UNIPROT IL1B protein P01584 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 17548584 YES svumbaca The loss of macrophage expression of HIF-1 led to significant decreases in the production of TNF-a, IL-1a, IL-1b, and IL-12 SIGNOR-256235 SIGNOR-MacroIL1BTR Macrophage: IL1 beta transcriptional regulation HIF1A protein Q16665 UNIPROT IL1B protein P01584 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 25750431 YES svumbaca The results of this study show that the absence of HIFs in MPs has no impact on the resolution of inflammation in two sterile models of skeletal muscle regeneration SIGNOR-256236 SIGNOR-MacroIL1BTR Macrophage: IL1 beta transcriptional regulation IRF5 protein Q13568 UNIPROT IL1B protein P01584 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000801 21240265 NO Among the genes with differences in expression in the M1 and M2 subsets are those regulated by IRF5, including IL12A, IL12B, IL23A, IL1B, TNF, CCL3(encoding MIP-1α), RANTES, CD1A, CD40, CD86 and CCR7 SIGNOR-254510 SIGNOR-MacroIL1BTR Macrophage: IL1 beta transcriptional regulation IRF5 protein Q13568 UNIPROT IL1B protein P01584 UNIPROT up-regulates transcriptional regulation 10090 26315890 NO svumbaca IL-1b was present in the sera of wild-type mice but was not detected in the sera of IRF5-/- mice SIGNOR-255340 SIGNOR-MacroIL4 Macrophage: IL4 SOCS1 protein O15524 UNIPROT JAK2 protein O60674 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 14522994 YES lperfetto Shp-2 regulates socs-1-mediated janus kinase-2 ubiquitination/degradation downstream of the prolactin receptor SIGNOR-118407 SIGNOR-MacroIL4 Macrophage: IL4 JAK2 protein O60674 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000599 9575217 YES lperfetto Activation of wild type stat3: il-6 treatment causes stat3 recruitment to receptor tyrosine phosphopeptides (gp130) where it is phosphorylated on tyrosine 705 (y) by jak kinase SIGNOR-236463 SIGNOR-MacroIL4 Macrophage: IL4 JAK2 protein O60674 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000599 9575217 YES lperfetto Inactive cytoplasmic STATs are recruited to the activated receptor by docking of the STAT SH2 domain to selected receptor tyrosine phosphopeptides, where they are in turn phosphorylated on a single tyrosine by Jak kinases. Has been identified tyrosine 705 of Stat3 as the likely site of phosphorylation by Jak kinases during signal transduction. SIGNOR-238638 SIGNOR-MacroIL4 Macrophage: IL4 JAK2 protein O60674 UNIPROT STAT6 protein P42226 UNIPROT up-regulates activity phosphorylation 9606 9852261 YES gcesareni Stat6 activation is mediated through jak1 and jak2 tyrosine kinases. SIGNOR-62585 SIGNOR-MacroIL4 Macrophage: IL4 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr637 KFGSLDTyLKKNKNC 9606 BTO:0000007 19364823 YES 16705160:The effect of Ser523 on Jak2 function was independent of Tyr570-mediated inhibition. lperfetto Analysis of in vitro autophosphorylated jak2while cytokine receptor stimulation mediates the phosphorylation of both tyr317 and tyr637, these residues oppositely regulate jak2-dependent signaling: the mutation of tyr317 enhances jak2 function, suggesting a role for the phosphorylation of tyr317 in the inhibition of jak2. Conversely, mutation of tyr637 reduces jak2 signaling, suggesting a role for the phosphorylation of this residue in the activation of jak2. SIGNOR-235885 SIGNOR-MacroIL4 Macrophage: IL4 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1007 VLPQDKEyYKVKEPG -1 9111318 YES Multiple autophosphorylation sites on Jak2, including Y1007 and Y1008. Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop. SIGNOR-251357 SIGNOR-MacroIL4 Macrophage: IL4 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr221 IRAKIQDyHILTRKR 9606 BTO:0000007 15143187 YES JAK2 is autophosphorylated on tyrosines 221 and 1007. tyrosines 221 and 570 in JAK2 may serve as regulatory sites in JAK2, with phosphorylation of tyrosine 221 increasing kinase activity and phosphorylation of tyrosine 570 decreasing kinase activity SIGNOR-251356 SIGNOR-MacroIL4 Macrophage: IL4 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT unknown phosphorylation Tyr1007 VLPQDKEyYKVKEPG -1 9111318 YES Within the Jak2 kinase domain, there is a region that has considerable sequence homology to the regulatory region of the insulin receptor and contains two tyrosines, Y1007 and Y1008, that are potential regulatory sites. Y1007 and Y1008 are sites of trans- or autophosphorylation in vivo and in in vitro kinase reactions. Mutation of Y1007, or both Y1007 and Y1008, to phenylalanine essentially eliminated kinase activity, whereas mutation of Y1008 to phenylalanine had no detectable effect on kinase activity SIGNOR-251358 SIGNOR-MacroIL4 Macrophage: IL4 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity phosphorylation Tyr570 VRREVGDyGQLHETE 9606 BTO:0000007 15143187 YES JAK2 is autophosphorylated on tyrosines 221 and 1007. tyrosines 221 and 570 in JAK2 may serve as regulatory sites in JAK2, with phosphorylation of tyrosine 221 increasing kinase activity and phosphorylation of tyrosine 570 decreasing kinase activity SIGNOR-251359 SIGNOR-MacroIL4 Macrophage: IL4 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr201 DQTPLAIyNSISYKT 9534 BTO:0000298 17027227 YES Site of Jak2 tyrosine autophosphorylation; namely, tyrosine 201. Jak2 tyrosine residue 201 was the principal mediator of SHP-2 binding as conversion of this tyrosine residue to phenylalanine abolished this interaction SIGNOR-251360 SIGNOR-MacroIL4 Macrophage: IL4 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr972 EYLGTKRyIHRDLAT 9606 BTO:0000007 20304997 YES lperfetto Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity SIGNOR-236294 SIGNOR-MacroIL4 Macrophage: IL4 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr813 NSLFTPDyELLTEND 9606 BTO:0000007 15121872 YES 16705160:The effect of Ser523 on Jak2 function was independent of Tyr570-mediated inhibition. lperfetto Tyrosine 813 is a site of jak2 autophosphorylation critical for activation of jak2 by sh2-b betawe show that phosphorylation of tyrosine 813 is required for the sh2 domain-containing adapter protein sh2-b beta to bind jak2 and to enhance the activity of jak2 and stat5b. SIGNOR-235910 SIGNOR-MacroIL4 Macrophage: IL4 KDM6B protein O15054 UNIPROT IRF4 protein Q15306 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 22025054 YES lperfetto JMJD3 seems to function by controlling expression of the transcription factor IRF4, which in turn is required for M2 polarization of macrophages in vitro and in vivo. Although this pathway is strongly supported by genetic. SIGNOR-249540 SIGNOR-MacroIL4 Macrophage: IL4 KDM6B protein O15054 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 22378047 NO lperfetto IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization. SIGNOR-249564 SIGNOR-MacroIL4 Macrophage: IL4 KDM6B protein O15054 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR down-regulates 9606 22378047 NO lperfetto IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization. SIGNOR-249563 SIGNOR-MacroIL4 Macrophage: IL4 PPARG protein P37231 UNIPROT STAT3 protein P40763 UNIPROT down-regulates 9606 BTO:0000801 17681149 NO lperfetto Transcriptional repression of inflammatory response genes occurs by negative interference of PPARg with the nuclear factor kB (NF-kB), signal transducer and activator of transcription (STAT), and activating protein 1 (AP-1) signaling pathways SIGNOR-249556 SIGNOR-MacroIL4 Macrophage: IL4 PPARG protein P37231 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 17681149 NO lperfetto This mechanism is mainly operative in native monocytes that, in the presence of an appropriate M2 stimulus such as IL-4, can be primed by PPARg ligands to an enhanced M2 phenotype. SIGNOR-249542 SIGNOR-MacroIL4 Macrophage: IL4 PPARG protein P37231 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates quantity by repression 9606 BTO:0000801 17681149 NO lperfetto Transcriptional repression of inflammatory response genes occurs by negative interference of PPARg with the nuclear factor kB (NF-kB), signal transducer and activator of transcription (STAT), and activating protein 1 (AP-1) signaling pathways SIGNOR-249555 SIGNOR-MacroIL4 Macrophage: IL4 IRF4 protein Q15306 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 20729857 NO lperfetto We found Irf4 to be one of the direct targets of Jmjd3-mediated demethylation. Finally, we found that Irf4 is a transcription factor crucial for the induction of M2 macrophage responses. SIGNOR-249543 SIGNOR-MacroIL4 Macrophage: IL4 IRF4 protein Q15306 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 22378047 NO lperfetto IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization. SIGNOR-249559 SIGNOR-MacroIL4 Macrophage: IL4 IRF4 protein Q15306 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR down-regulates 9606 22378047 NO lperfetto IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization. SIGNOR-249561 SIGNOR-MacroIL4 Macrophage: IL4 STAT6 protein P42226 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 20508200 NO lperfetto Phosphorylated STAT6 dimerizes and translocates to the nucleus where it induces the expression of its target genes, including markers (Arg1, Chi3l3, Mrc1, Mgl1, and Retnla) and regulators (Pparalpha, Ppargamma and PGC-1?) of alternative activation. SIGNOR-249533 SIGNOR-MacroIL4 Macrophage: IL4 STAT6 protein P42226 UNIPROT KDM6B protein O15054 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19567879 NO lperfetto We demonstrate that IL-4dependent Jmjd3 expression is mediated by STAT6, a major transcription factor of IL-4mediated signaling. After IL-4 stimulation, activated STAT6 is increased and binds to consensus sites at the Jmjd3 promoter. SIGNOR-249539 SIGNOR-MacroIL4 Macrophage: IL4 STAT6 protein P42226 UNIPROT SOCS1 protein O15524 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17093501 YES lperfetto We found that IL-4, like IFN-gamma, induces rapid de novo expression of SOCS-1 in primary macrophages. Induction of SOCS-1 gene expression by IL-4 is STAT6-dependent. SIGNOR-249570 SIGNOR-MacroIL4 Macrophage: IL4 STAT6 protein P42226 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 22025054 NO lperfetto IL-4R signals through a JAKSTAT6 pathway, and many of the genes associated with mouse M2 macrophages are regulated by STAT6, including arginase 1 (Arg1), macrophage mannose receptor 1 (Mrc1; also known as Cd206), resistin-like-? (Retnla; also known as Fizz1) and chitinase 3-like 3 (Chi3l3; also known as Ym1). SIGNOR-249541 SIGNOR-MacroIL4 Macrophage: IL4 STAT6 protein P42226 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 BTO:0000801 10982806 YES lperfetto STAT6 mediates suppression of STAT1 and NF-kB-dependent transcription by distinct mechanisms. Both processes are dependent upon the STAT6 transactivation domain and may involve sequestration of necessary but different transcriptional coactivator proteins. These two suppressive mechanisms are controlled differentially by the nature of the STAT6 DNA-binding site SIGNOR-249553 SIGNOR-MacroIL4 Macrophage: IL4 IL4 protein P05112 UNIPROT IL4R protein P24394 UNIPROT up-regulates activity binding 9606 BTO:0000801 18852293 YES lperfetto IL-4 signals through the type I (IL-4Ralpha/common gamma-chain [gammac]) and the type II (IL-4Ralpha/-13Ralpha1) IL-4 receptors, whereas IL-13 utilizes only the type II receptor. SIGNOR-249527 SIGNOR-MacroIL4 Macrophage: IL4 IL4 protein P05112 UNIPROT IL4R protein P24394 UNIPROT up-regulates binding -1 10219247 YES gcesareni Nterleukin-4 (il-4) is a principal regulatory cytokine during an immune response and a crucial determinant for allergy and asthma. Il-4 binds with high affinity and specificity to the ectodomain of the il-4 receptor alpha chain (il4-bp). SIGNOR-67217 SIGNOR-MacroIL4 Macrophage: IL4 IL4 protein P05112 UNIPROT IL4R protein P24394 UNIPROT up-regulates binding 9606 12704343 YES milica IL-4R Is a 140-kd protein that binds il-4 with high affinity SIGNOR-100762 SIGNOR-MacroIL4 Macrophage: IL4 IL13 protein P35225 UNIPROT IL4R protein P24394 UNIPROT up-regulates binding 9606 12704343 YES milica Both il-4 and il-13 use the IL-4R Chain as a component of their receptors. SIGNOR-100753 SIGNOR-MacroIL4 Macrophage: IL4 IL4R protein P24394 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 18852293 YES lperfetto Downstream intracellular signaling from the IL-4IL-4Rc complex involves activation of the Jak1 and Jak3 kinases, phosphorylation of the Stat6 transcription factor, and activation of the insulin receptor substrate (IRS)-2 and Dok2-signaling intermediates. IL-13 initially binds to IL-13R1 with intermediate affinity, and then heterodimerizes with IL-4R. The IL-13IL-13R1IL-4R complex activates the Tyk2, Jak2, and Jak1 kinases and Stat6. SIGNOR-249530 SIGNOR-MacroIL6 Macrophage: IL6 SOCS1 protein O15524 UNIPROT JAK1 protein P23458 UNIPROT down-regulates binding 9606 23663276 YES milica Socs1 and socs3 target jak1 and gp130, respectively, near the plasma membrane to prevent cytoplasmic stats from being activated, whereas pias1 principally targets activated stat1 in the cell nucleus and prevents it from binding to dna. SIGNOR-202042 SIGNOR-MacroIL6 Macrophage: IL6 SOCS1 protein O15524 UNIPROT JAK1 protein P23458 UNIPROT down-regulates binding 9606 11133764 YES gcesareni Jab/socs1/ssi-1 is an il-2 induced inhibitor of il-2 signaling that functions by inhibiting jak kinase activity SIGNOR-85352 SIGNOR-MacroIL6 Macrophage: IL6 IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 23663276 YES milica In classical il-6 signaling, the cytokine first binds to the membrane-bound il-6 receptor (il-6r;cd126) that is induced to associate with a homodimer of gp130 which then transmits the intracellular signal. SIGNOR-202030 SIGNOR-MacroIL6 Macrophage: IL6 IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 15895091 YES gcesareni We show that the augmentation of the il6 signal by recombinant il6 receptors (ril6r) delivery allows the functional recovery of phagocytes in a peritonitis mouse model. SIGNOR-137236 SIGNOR-MacroIL6 Macrophage: IL6 IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 8676083 YES fspada We first observed that cultured mouse embryonic dorsal root ganglia exhibited dramatic neurite extension by simultaneous addition of il-6 and soluble il-6r (sil-6r), a complex that is known to interact with and activate a signal transducing receptor component, gp130 SIGNOR-42866 SIGNOR-MacroIL6 Macrophage: IL6 JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 19723038 YES lperfetto The activation of stat-3 is regulated by phosphorylation of tyrosine 705 by receptor and nonreceptor protein tyrosine kinases. These include epidermal growth factor receptor (egfr) kinase, src, janus-activated kinases (jak), and extracellular signal-regulated kinase (erk). SIGNOR-187775 SIGNOR-MacroIL6 Macrophage: IL6 JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity binding 9606 24710148 YES lperfetto The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3). SIGNOR-236369 SIGNOR-MacroIL6 Macrophage: IL6 STAT3 protein P40763 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 10347215 NO lperfetto The data presented this far show that the JAK-STAT signaling pathway and specifically Stat3 and Jak1 are required for induction of IL-10-dependent anti-inflammatory and developmental responses in macrophages. SIGNOR-249547 SIGNOR-MacroIL6 Macrophage: IL6 IL6R protein P08887 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 23663276 YES milica In classical il-6 signaling, the cytokine first binds to the membrane-bound il-6 receptor (il-6r;cd126) that is induced to associate with a homodimer of gp130 which then transmits the intracellular signal. SIGNOR-202033 SIGNOR-MacroIL6 Macrophage: IL6 IL6R protein P08887 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 BTO:0000785 11238858 YES gcesareni Part of the receptor for interleukin 6. Binds to il6 with low affinity, but does not transduce a signal. Signal activation necessitate an association with il6st. Activation may lead to the regulation of the immune response, acute-phase reactions and hematopoiesis. SIGNOR-105504 SIGNOR-MacroIL6 Macrophage: IL6 IL6ST protein P40189 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity phosphorylation Ser661 NVPDPSKsHIAQWSP -1 8511589 YES lperfetto The biological functions of interleukin-6 (IL-6) are mediated through a signal-transducing component of the IL-6 receptor, gp130, which is associated with the ligand-occupied IL-6 receptor (IL-6R) protein. Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130. Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein. Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130. SIGNOR-238625 SIGNOR-MacroIL6 Macrophage: IL6 IL6ST protein P40189 UNIPROT JAK1 protein P23458 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 23663276 YES milica Il-6 family members typically signal through the common gp130 receptor, with the janus kinase/signal transducer and activator of transcription (jak/stat) pathway being the major intracellular mediator of their effects. SIGNOR-202036 SIGNOR-MacroIL6 Macrophage: IL6 IL6ST protein P40189 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 24710148 YES milica The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3). SIGNOR-204841 SIGNOR-MacroMS Macrophage: Metabolic switch L-ornithine smallmolecule CHEBI:15729 ChEBI M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates activity 25386178 NO apalma In general, M2 type macrophages act as anti-inflammatory cells via diversion of arginine away from NOS or via the synthesis of downstream products derived from the ornithine that is generated via arginase SIGNOR-256075 SIGNOR-MacroMS Macrophage: Metabolic switch L-ornithine smallmolecule CHEBI:15729 ChEBI M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates activity 24669294 NO apalma While investigating the factors that regulate macrophage arginine metabolism, Mills and colleagues found that macrophages activated in mouse strains with Th1 and Th2 backgrounds differed qualitatively in their ability to respond to the classic stimuli IFN-γ or lipopolysaccharide (LPS) or both and defined an important metabolic difference in the pathway: M1 macrophages made the toxic nitric oxide (NO), whereas M2 macrophages made the trophic polyamines SIGNOR-256076 SIGNOR-MacroMS Macrophage: Metabolic switch L-arginine chemical CHEBI:16467 ChEBI ARG1 protein P05089 UNIPROT up-regulates BTO:0000801 BTO:0001103 25386178 NO apalma In mammalian cells, arginine can be catabolized by four classes of enzymes (Figure ​(Figure1):1): NOS, arginase, arginine decarboxylase (ADC), and arginine:glycine amidinotransferase (AGAT) SIGNOR-255555 SIGNOR-MacroMS Macrophage: Metabolic switch L-arginine chemical CHEBI:16467 ChEBI NOS2 protein P35228 UNIPROT up-regulates BTO:0000801 BTO:0001103 25386178 NO apalma In mammalian cells, arginine can be catabolized by four classes of enzymes (Figure ​(Figure1):1): NOS, arginase, arginine decarboxylase (ADC), and arginine:glycine amidinotransferase (AGAT) SIGNOR-255554 SIGNOR-MacroMS Macrophage: Metabolic switch nitric oxide smallmolecule CHEBI:16480 ChEBI M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 24669294 NO apalma While investigating the factors that regulate macrophage arginine metabolism, Mills and colleagues found that macrophages activated in mouse strains with Th1 and Th2 backgrounds differed qualitatively in their ability to respond to the classic stimuli IFN-γ or lipopolysaccharide (LPS) or both and defined an important metabolic difference in the pathway: M1 macrophages made the toxic nitric oxide (NO), whereas M2 macrophages made the trophic polyamines SIGNOR-255556 SIGNOR-MacroMS Macrophage: Metabolic switch NOS2 protein P35228 UNIPROT nitric oxide smallmolecule CHEBI:16480 ChEBI up-regulates 9606 7537672 NO apalma Activation with lipopolysaccharide induces macrophages to produce the enzymes arginase and nitric oxide (NO) synthase. Both enzymes use as a substrate the ammino acid L-arginine, which can be either hydrolyzed by arginase to urea and ornithine or oxidized by NO synthase to NO and citrulline SIGNOR-255381 SIGNOR-MacroMS Macrophage: Metabolic switch STAT6 protein P42226 UNIPROT ARG1 protein P05089 UNIPROT up-regulates BTO:0000801 BTO:0001103 25386178 NO apalma Cytokines like IL-4 or IL-13 lead to STAT6 phosphorylation with consecutive arginase expression and varying further aspects of M2 polarization (mannose receptor, Ym1, Fizz1) SIGNOR-255557 SIGNOR-MacroMS Macrophage: Metabolic switch ARG1 protein P05089 UNIPROT L-ornithine smallmolecule CHEBI:15729 ChEBI up-regulates quantity chemical modification 9606 14617280 YES miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) SIGNOR-255545 SIGNOR-MacroPol Macrophage: Polarization and myogenesis NfKb-p65/p50 complex SIGNOR-C13 SIGNOR SOCS3 protein O14543 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19643666 YES lperfetto Expression of SOCS1 and SOCS3 is regulated primarily by activation of STAT1 and STAT3, respectively, although their expression can be mediated through other signaling cascades, including the mitogen activated protein kinase (MAPK) and nuclear factor-kappa B (NF-kappaB) pathways. SIGNOR-249566 SIGNOR-MacroPol Macrophage: Polarization and myogenesis NfKb-p65/p50 complex SIGNOR-C13 SIGNOR M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 9606 30060484 NO miannu The bacterial endotoxin LPS is a known agonist of TLR2 that activates the expression of proinflammatory cytokines and the phosphorylation of MAPKs and NFκB [49]. In addition, the activation of the MAPK and NFκB signaling cascades drive inflammation and macrophage polarization.  SIGNOR-249519 SIGNOR-MacroPol Macrophage: Polarization and myogenesis SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 22703233 NO lperfetto Our results establish a novel biological role for TGFbeta signaling in controlling expression of genes characteristic for alternatively activated macrophages. We speculate that lack of TbetaRII signaling reduces the anti-inflammatory M2 phenotype of macrophages because of reduced expression of these products. SIGNOR-249550 SIGNOR-MacroPol Macrophage: Polarization and myogenesis SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 27418133 NO The SMAD2/3 and PI3K/AKT signaling pathways were crucial for TGF-?-induced SNAIL overexpression in THP-1 cells. These findings suggest that TGF-? skews macrophage polarization towards a M2-like phenotype via SNAIL up-regulation, and blockade of TGF-?/SNAIL signaling restores the production of pro-inflammatory cytokines SIGNOR-253588 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 BTO:0000007 19609947 YES lperfetto Our data suggest that the stimulation of nfkb by akt is dependent on the phosphorylation of p65 at s534, mediated by ikk (ikb kinase) alfa and beta. SIGNOR-216365 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 15489227 YES lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. SIGNOR-216341 SIGNOR-MacroPol Macrophage: Polarization and myogenesis TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT up-regulates activity binding 9606 17151142 YES miannu TNF-α has two distinct plasma membrane receptors known as p55 and p75. These data indicate that myogenic activation of p38 requires TNF-alpha receptor-mediated signaling SIGNOR-253591 SIGNOR-MacroPol Macrophage: Polarization and myogenesis TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT up-regulates activity binding 9606 14732063 YES miannu Tumour necrosis factor (TNF) exerts two main effects: a beneficial one as an anti-infection, anti-tumour cytokine, and a detrimental one in the systemic inflammatory response syndrome (SIRS). Two receptors (TNF-R) mediate these effects. two distinct types of TNF-Rs have been identified and molecularly cloned: TNF-R55 (also referred to as TNFR1, p55 or CD120a) and TNF-R75 (also called TNFR2, p75 or CD120b) SIGNOR-253593 SIGNOR-MacroPol Macrophage: Polarization and myogenesis TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT up-regulates activity binding 9606 11502070 YES lperfetto Binding of tnf to the extracellular domain of tnfrsf1a leads to homotrimerization. SIGNOR-109716 SIGNOR-MacroPol Macrophage: Polarization and myogenesis TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT up-regulates activity binding 9606 23070005 YES miannu For TNFR1, the cytokine TNFα binds to the receptor and triggers its trimerization, which leads to the assembly of the receptor complex and initiation of signaling. SIGNOR-199091 SIGNOR-MacroPol Macrophage: Polarization and myogenesis TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT up-regulates activity binding 9606 10634209 YES lperfetto TNF-induced apoptosis is mediated primarily through the activation of type I receptors SIGNOR-226676 SIGNOR-MacroPol Macrophage: Polarization and myogenesis TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity binding 9606 22326956 YES lperfetto TGF-beta signaling mediates a wide range of biological activities in development and disease. TGF-beta ligands signal through heterodimeric type I and type II receptors (TGF-beta receptor type I [TbetaRI, also known as ALK5 and TGFBR1] and TbetaRII) that are members of the serine/threonine kinase family. SIGNOR-196022 SIGNOR-MacroPol Macrophage: Polarization and myogenesis TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates binding 9606 26194464 YES MARCO ROSINA TGF-b ligands bind to TGF-b type II receptor (TbRII), which transphosphorylates and activates TGF-b type I receptor (TbRI). SIGNOR-255031 SIGNOR-MacroPol Macrophage: Polarization and myogenesis TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity binding 9606 22703233 YES lperfetto TGFbeta signals are transmitted via a cell surface receptor complex consisting of the TGFbeta type I receptor (TbetaRI) and TGFbeta type II receptor (TbetaRII). To initiate signal transduction, TGFbeta binds to TbetaRII, which in turn recruits TbetaRI, leading to the formation of a tetrameric receptor complex. SIGNOR-249548 SIGNOR-MacroPol Macrophage: Polarization and myogenesis SOCS3 protein O14543 UNIPROT IL6ST protein P40189 UNIPROT down-regulates activity binding 9606 23454976 YES miannu SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition. The inhibitory protein SOCS3 plays a key part in the immune and hematopoietic systems by regulating signaling induced by specific cytokines. SOCS3 functions by inhibiting the catalytic activity of Janus kinases (JAKs) that initiate signaling within the cell. SIGNOR-255328 SIGNOR-MacroPol Macrophage: Polarization and myogenesis SOCS3 protein O14543 UNIPROT IL6ST protein P40189 UNIPROT down-regulates activity binding 9606 BTO:0000887;BTO:0001103 19620279 YES miannu We now show that SOCS1, SOCS3, and PIAS1 promote myogenic differentiation by specifically inhibiting the LIF-induced JAK1/STAT1/STAT3 pathway via distinct targets; whereas SOCS1 and SOCS3 selectively bind and inhibit JAK1 and gp130, respectively, PIAS1 targets mainly the activated STAT1 and prevents its binding to DNA. SIGNOR-202045 SIGNOR-MacroPol Macrophage: Polarization and myogenesis SOCS3 protein O14543 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity 9606 24600449 NO miannu A main role of SOCS3 results from its binding to both the JAK kinase and the cytokine receptor, which results in the inhibition of STAT3 activation. SIGNOR-255330 SIGNOR-MacroPol Macrophage: Polarization and myogenesis SOCS3 protein O14543 UNIPROT STAT3 protein P40763 UNIPROT down-regulates 9606 BTO:0000801 21628332 NO lperfetto SOCS3 attenuates IL-6-induced STAT3 anti-inflammatory effects, as well as IL-4-induced insulin receptor substrate-2/PI3K-mediated gene expression. SIGNOR-249567 SIGNOR-MacroPol Macrophage: Polarization and myogenesis SOCS3 protein O14543 UNIPROT JAK1 protein P23458 UNIPROT down-regulates activity binding 9606 23454976 YES miannu SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition SIGNOR-253051 SIGNOR-MacroPol Macrophage: Polarization and myogenesis SOCS3 protein O14543 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity binding 9606 24600449 YES miannu The ability of SOCS3 to simultaneously bind to JAK and to the cytokine receptor explains the specificity of the suppression. SOCS3 binds JAK and gp130 receptor simultaneously, using two opposing surfaces: while the phosphotyrosine-binding groove on the SOCS3 SH2 domain is occupied by the gp130 receptor, a subdomain in the SH2 domain of SOCS3 is also required for inhibition of JAK, binding in a phospho-independent manner to a non-canonical surface of JAK2 (58, 59). The KIR of SOCS3 occludes the substrate-binding groove on JAK2. SIGNOR-255329 SIGNOR-MacroPol Macrophage: Polarization and myogenesis SOCS3 protein O14543 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates 9606 16543409 NO lperfetto Suppressor of cytokine signaling (SOCS)-3 was shown to inhibit IL-1-induced transcription and activation of NFkappaB and the MAPKs JNK and p38, but the mechanism is unknown SIGNOR-253052 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL1B protein P01584 UNIPROT IL1R1 protein P14778 UNIPROT up-regulates activity binding 9606 BTO:0000801 24166242 YES lperfetto Pro-IL-1beta, mIL-1beta and mIL-beta all bind to IL-1RI, which recruits the IL-1 receptor accessory protein (IL-1RAcP) as a co-receptor. SIGNOR-249511 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL1B protein P01584 UNIPROT IL1R1 protein P14778 UNIPROT up-regulates binding 9606 BTO:0001253 9625767 YES gcesareni Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab). SIGNOR-58122 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL1R1 protein P14778 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity 9606 BTO:0000007 14625308 NO lperfetto Formation of the signaling il-1 receptor complex results in the activation and hyperphosphorylation of irak-1. SIGNOR-119208 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL1R1 protein P14778 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity 9606 9625767 NO lperfetto Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab) SIGNOR-249512 SIGNOR-MacroPol Macrophage: Polarization and myogenesis SMAD2 protein Q15796 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates activity binding 9606 phosphorylation:Ser465;Ser467 SPSVRCSsMS;SVRCSSMs 11274206 YES gcesareni the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4 SIGNOR-235183 SIGNOR-MacroPol Macrophage: Polarization and myogenesis SMAD2 protein Q15796 UNIPROT SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR form complex binding 9606 phosphorylation:Ser465;Ser467 SPSVRCSsMS;SVRCSSMs 11274206 YES gcesareni the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4 SIGNOR-235188 SIGNOR-MacroPol Macrophage: Polarization and myogenesis SMAD4 protein Q13485 UNIPROT SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR form complex binding 9606 11274206 YES gcesareni the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4 SIGNOR-235178 SIGNOR-MacroPol Macrophage: Polarization and myogenesis SMAD3 protein P84022 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates activity binding 9606 9843571 YES gcesareni TGF-² treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. SIGNOR-235168 SIGNOR-MacroPol Macrophage: Polarization and myogenesis SOCS1 protein O15524 UNIPROT IRAK1 protein P51617 UNIPROT down-regulates binding 9606 12433373 YES flangone Coimmunoprecipitation analyses demonstrated association of socs-1 with irak...This Finding suggests that socs-1 might suppress myd88-dependent signal pathways at least by binding to irak SIGNOR-95528 SIGNOR-MacroPol Macrophage: Polarization and myogenesis SOCS1 protein O15524 UNIPROT JAK1 protein P23458 UNIPROT down-regulates binding 9606 23663276 YES milica Socs1 and socs3 target jak1 and gp130, respectively, near the plasma membrane to prevent cytoplasmic stats from being activated, whereas pias1 principally targets activated stat1 in the cell nucleus and prevents it from binding to dna. SIGNOR-202042 SIGNOR-MacroPol Macrophage: Polarization and myogenesis SOCS1 protein O15524 UNIPROT JAK1 protein P23458 UNIPROT down-regulates binding 9606 11133764 YES gcesareni Jab/socs1/ssi-1 is an il-2 induced inhibitor of il-2 signaling that functions by inhibiting jak kinase activity SIGNOR-85352 SIGNOR-MacroPol Macrophage: Polarization and myogenesis SOCS1 protein O15524 UNIPROT STAT1 protein P42224 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16628196 NO miannu SOCS1, which is another inducible gene, not only blocks STAT1 activation but also inhibits STAT1-dependent TLR3, IRF-7, and MIP-1α. SIGNOR-255229 SIGNOR-MacroPol Macrophage: Polarization and myogenesis SOCS1 protein O15524 UNIPROT JAK2 protein O60674 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 14522994 YES lperfetto Shp-2 regulates socs-1-mediated janus kinase-2 ubiquitination/degradation downstream of the prolactin receptor SIGNOR-118407 SIGNOR-MacroPol Macrophage: Polarization and myogenesis JAK2 protein O60674 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation 7888666 YES apalma We found that IL-5 induced two GAS-binding proteins in the nuclear extract from eosinophils. One of them was identified as STAT1 (p91). SIGNOR-255071 SIGNOR-MacroPol Macrophage: Polarization and myogenesis JAK2 protein O60674 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000567 15322115 YES lperfetto Phosphorylation at tyr701 by the janus family of tyrosine kinases (jak) leads to stat1 dimerization via its src homology 2 domains, exposure of a dimer-specific nuclear localization signal, and subsequent nuclear translocation. SIGNOR-235709 SIGNOR-MacroPol Macrophage: Polarization and myogenesis JAK2 protein O60674 UNIPROT STAT6 protein P42226 UNIPROT up-regulates activity phosphorylation 9606 9852261 YES gcesareni Stat6 activation is mediated through jak1 and jak2 tyrosine kinases. SIGNOR-62585 SIGNOR-MacroPol Macrophage: Polarization and myogenesis JAK2 protein O60674 UNIPROT STAT6 protein P42226 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 18852293 YES lperfetto Downstream intracellular signaling from the IL-4IL-4Rc complex involves activation of the Jak1 and Jak3 kinases, phosphorylation of the Stat6 transcription factor, and activation of the insulin receptor substrate (IRS)-2 and Dok2-signaling intermediates. IL-13 initially binds to IL-13R1 with intermediate affinity, and then heterodimerizes with IL-4R. The IL-13IL-13R1IL-4R complex activates the Tyk2, Jak2, and Jak1 kinases and Stat6. SIGNOR-249532 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL6 protein P05231 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity -1 8511589 NO lperfetto The biological functions of interleukin-6 (IL-6) are mediated through a signal-transducing component of the IL-6 receptor, gp130, which is associated with the ligand-occupied IL-6 receptor (IL-6R) protein. Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130. Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein. Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130. SIGNOR-238617 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL6 protein P05231 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity binding 9606 BTO:0001271 15895091 YES miannu A crystal structure of the ligand-binding domains of gp130 in complex with human interleukin-6 (il-6) and its a-receptor (il-6ralpha) revealed a hexameric architecture in which the gp130 membrane-distal regions were approximately 100 a apart, in contrast to the close apposition seen between short cytokine receptor complexes. SIGNOR-48041 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates activity binding 9606 18923185 YES miannu IL-6 and IL-11 are the only members of the family that signal via the induction of a gp130 homodimer after binding their specific -receptors, IL-6R and IL-11R. When IL-6 binds to the homodimerized IL-6Rα/gp130Rβ, it results in a signaling cascade that is initiated by the autophoshorylation and activation of JAK. SIGNOR-255324 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 23663276 YES milica In classical il-6 signaling, the cytokine first binds to the membrane-bound il-6 receptor (il-6r;cd126) that is induced to associate with a homodimer of gp130 which then transmits the intracellular signal. SIGNOR-202030 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 15895091 YES gcesareni We show that the augmentation of the il6 signal by recombinant il6 receptors (ril6r) delivery allows the functional recovery of phagocytes in a peritonitis mouse model. SIGNOR-137236 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 8676083 YES fspada We first observed that cultured mouse embryonic dorsal root ganglia exhibited dramatic neurite extension by simultaneous addition of il-6 and soluble il-6r (sil-6r), a complex that is known to interact with and activate a signal transducing receptor component, gp130 SIGNOR-42866 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL6 protein P05231 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity 10116 BTO:0001103 23869758 NO andrea cerquone perpetuini IL-6 induced dose-dependent increase in satellite cell proliferation by activating the JAK2/STAT3/cyclin D1 pathway.Treatment with 1 ng/ml IL-6 for 3 h significantly increased p-STAT3+/MyoD+ cell numbers by 44% compared to control media only . SIGNOR-255415 SIGNOR-MacroPol Macrophage: Polarization and myogenesis RIPK1 protein Q13546 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates activity binding 10090 BTO:0000452 10795740 YES gcesareni We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation SIGNOR-245026 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL10 protein P22301 UNIPROT IL10RA protein Q13651 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0000776 10347215 YES milica Functionally active il-10 receptors are composed of two distinct subunits. The il-10 receptor ? Chain is a 110-kda polypeptide that plays the dominant role in mediating high affinity ligand binding and signal transduction. The il-10 receptor ? Subunit (also known as crf2_4) is predicted to be a 40-kda polypeptide that is largely required only for signaling SIGNOR-67964 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL10 protein P22301 UNIPROT IL10RA protein Q13651 UNIPROT up-regulates activity binding 9606 BTO:0000801 26260587 YES lperfetto IL10 is a classic anti-inflammatory cytokine and its molecular signalling pathway has been well characterized in macrophages and T lymphocytes. Secreted IL10 cytokine binds to the IL10 receptor 1 (IL10R1) on membrane surfaces, and IL10R1 dimerizes with IL10R2 to exert its downstream effects. SIGNOR-249544 SIGNOR-MacroPol Macrophage: Polarization and myogenesis PPARG protein P37231 UNIPROT STAT3 protein P40763 UNIPROT down-regulates 9606 BTO:0000801 17681149 NO lperfetto Transcriptional repression of inflammatory response genes occurs by negative interference of PPARg with the nuclear factor kB (NF-kB), signal transducer and activator of transcription (STAT), and activating protein 1 (AP-1) signaling pathways SIGNOR-249556 SIGNOR-MacroPol Macrophage: Polarization and myogenesis PPARG protein P37231 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 17681149 NO lperfetto This mechanism is mainly operative in native monocytes that, in the presence of an appropriate M2 stimulus such as IL-4, can be primed by PPARg ligands to an enhanced M2 phenotype. SIGNOR-249542 SIGNOR-MacroPol Macrophage: Polarization and myogenesis PPARG protein P37231 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates quantity by repression 9606 BTO:0000801 17681149 NO lperfetto Transcriptional repression of inflammatory response genes occurs by negative interference of PPARg with the nuclear factor kB (NF-kB), signal transducer and activator of transcription (STAT), and activating protein 1 (AP-1) signaling pathways SIGNOR-249555 SIGNOR-MacroPol Macrophage: Polarization and myogenesis TRADD protein Q15628 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 8612133 YES lperfetto We show that tradd interacts strongly with rip;rip is a serinethreonine kinase that is recruited by tradd to tnfr1 in a tnf-dependent process. SIGNOR-40043 SIGNOR-MacroPol Macrophage: Polarization and myogenesis STAT6 protein P42226 UNIPROT STAT1 protein P42224 UNIPROT down-regulates activity binding 9606 BTO:0000801 10982806 YES lperfetto STAT6 mediates suppression of STAT1 and NF-kB-dependent transcription by distinct mechanisms. Both processes are dependent upon the STAT6 transactivation domain and may involve sequestration of necessary but different transcriptional coactivator proteins. These two suppressive mechanisms are controlled differentially by the nature of the STAT6 DNA-binding site SIGNOR-249552 SIGNOR-MacroPol Macrophage: Polarization and myogenesis STAT6 protein P42226 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 20508200 NO lperfetto Phosphorylated STAT6 dimerizes and translocates to the nucleus where it induces the expression of its target genes, including markers (Arg1, Chi3l3, Mrc1, Mgl1, and Retnla) and regulators (Pparalpha, Ppargamma and PGC-1?) of alternative activation. SIGNOR-249533 SIGNOR-MacroPol Macrophage: Polarization and myogenesis STAT6 protein P42226 UNIPROT SOCS1 protein O15524 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17093501 YES lperfetto We found that IL-4, like IFN-gamma, induces rapid de novo expression of SOCS-1 in primary macrophages. Induction of SOCS-1 gene expression by IL-4 is STAT6-dependent. SIGNOR-249570 SIGNOR-MacroPol Macrophage: Polarization and myogenesis STAT6 protein P42226 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 22025054 NO lperfetto IL-4R signals through a JAKSTAT6 pathway, and many of the genes associated with mouse M2 macrophages are regulated by STAT6, including arginase 1 (Arg1), macrophage mannose receptor 1 (Mrc1; also known as Cd206), resistin-like-? (Retnla; also known as Fizz1) and chitinase 3-like 3 (Chi3l3; also known as Ym1). SIGNOR-249541 SIGNOR-MacroPol Macrophage: Polarization and myogenesis STAT6 protein P42226 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 BTO:0000801 10982806 YES lperfetto STAT6 mediates suppression of STAT1 and NF-kB-dependent transcription by distinct mechanisms. Both processes are dependent upon the STAT6 transactivation domain and may involve sequestration of necessary but different transcriptional coactivator proteins. These two suppressive mechanisms are controlled differentially by the nature of the STAT6 DNA-binding site SIGNOR-249553 SIGNOR-MacroPol Macrophage: Polarization and myogenesis STAT1 protein P42224 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity binding 9606 19041276 YES lperfetto Each STAT1 monomer becomes tyrosine phosphorylated at tyrosine 701 by the JAKs, dissociates from the receptor to form a STAT1-STAT1 homodimer which translocates to the nucleus SIGNOR-249495 SIGNOR-MacroPol Macrophage: Polarization and myogenesis STAT1 protein P42224 UNIPROT SOCS1 protein O15524 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19482358 NO miannu Socs1 expression is induced in the human keratinocytes HaCaT cell line through sequential activation of STAT1 and IRF-1 SIGNOR-226484 SIGNOR-MacroPol Macrophage: Polarization and myogenesis STAT1 protein P42224 UNIPROT SOCS3 protein O14543 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19643666 YES lperfetto Expression of SOCS1 and SOCS3 is regulated primarily by activation of STAT1 and STAT3, respectively, although their expression can be mediated through other signaling cascades, including the mitogen activated protein kinase (MAPK) and nuclear factor-kappa B (NF-kappaB) pathways. SIGNOR-249565 SIGNOR-MacroPol Macrophage: Polarization and myogenesis STAT1 protein P42224 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 9606 19029990 NO lperfetto STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others. SIGNOR-249496 SIGNOR-MacroPol Macrophage: Polarization and myogenesis JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 9606 26260587 YES IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes. SIGNOR-253590 SIGNOR-MacroPol Macrophage: Polarization and myogenesis JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 19723038 YES lperfetto The activation of stat-3 is regulated by phosphorylation of tyrosine 705 by receptor and nonreceptor protein tyrosine kinases. These include epidermal growth factor receptor (egfr) kinase, src, janus-activated kinases (jak), and extracellular signal-regulated kinase (erk). SIGNOR-187775 SIGNOR-MacroPol Macrophage: Polarization and myogenesis JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity binding 9606 24710148 YES lperfetto The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3). SIGNOR-236369 SIGNOR-MacroPol Macrophage: Polarization and myogenesis JAK1 protein P23458 UNIPROT IL10RA protein Q13651 UNIPROT up-regulates activity phosphorylation Tyr446 AAVAFQGyLRQTRCA 10433356 YES Binding of IL-10 to the extracellular domain of IL-10R1 activates phosphorylation of the receptor-associated Janus tyrosine kinases, JAK1 and Tyk2. These kinases then phosphorylate specific tyrosine residues (Y446 and Y496) on the intracellular domain of the IL-10R1 chain. Once phosphorylated, these tyrosine residues (and their flanking peptide sequences) serve as temporary docking sites for the latent transcription factor, STAT3 (signal transducer and activator of transcription-3). SIGNOR-251338 SIGNOR-MacroPol Macrophage: Polarization and myogenesis JAK1 protein P23458 UNIPROT IL10RA protein Q13651 UNIPROT up-regulates activity phosphorylation Tyr496 PPALAKGyLKQDPLE 10433356 YES Binding of IL-10 to the extracellular domain of IL-10R1 activates phosphorylation of the receptor-associated Janus tyrosine kinases, JAK1 and Tyk2. These kinases then phosphorylate specific tyrosine residues (Y446 and Y496) on the intracellular domain of the IL-10R1 chain. Once phosphorylated, these tyrosine residues (and their flanking peptide sequences) serve as temporary docking sites for the latent transcription factor, STAT3 (signal transducer and activator of transcription-3). SIGNOR-251339 SIGNOR-MacroPol Macrophage: Polarization and myogenesis JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS -1 7657660 YES lperfetto Stat1 was phosphorylated at tyr 701 in jak immune complex kinase reaction. The stat1 and stat2 proteins are present in the cytoplasm of untreated cells;upon stimulation with ifn-g, They become rapidly activated by tyrosine phosphorylation at a single site catalyzed by receptor associated jak (janus) kinases. SIGNOR-30905 SIGNOR-MacroPol Macrophage: Polarization and myogenesis JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 9020188 YES lperfetto The stat1 and stat2 proteins are present in the cytoplasm of untreated cells;upon stimulation with ifn-g they become rapidly activated by tyrosine phosphorylation at a single site catalyzed by receptor associated jak (janus) kinases. SIGNOR-236239 SIGNOR-MacroPol Macrophage: Polarization and myogenesis JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000567 11823427 YES lperfetto The central event in cytokine_dependent transcriptional regulation is phosphorylation of STATs on a single tyrosine residue at their C_terminus (Darnell, 1997b). The reaction is catalyzed by cytokine receptor_associated tyrosine kinases of the Janus type (Jak) at the cell membrane and triggers the homo_ and heterodimerization of STAT molecules via reciprocal phosphotyrosine“SH2 domain interactions SIGNOR-236373 SIGNOR-MacroPol Macrophage: Polarization and myogenesis JAK1 protein P23458 UNIPROT STAT6 protein P42226 UNIPROT up-regulates activity phosphorylation 9606 9852261 YES gcesareni Stat6 activation is mediated through jak1 and jak2 tyrosine kinases SIGNOR-62582 SIGNOR-MacroPol Macrophage: Polarization and myogenesis JAK1 protein P23458 UNIPROT STAT6 protein P42226 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 23124025 YES lperfetto IL-4-stimulated Stat6 activation is mediated by Jak1 whereas Tyk2 is required for Stat6 activation in IL-13-treated monocytes SIGNOR-249531 SIGNOR-MacroPol Macrophage: Polarization and myogenesis TNFRSF1A protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 10090 BTO:0002572;BTO:0000801 21232017 YES miannu TRADD and RIP1 contain a C‐terminal death domain which mediates binding to the death domain of TNFR1. Upon association with ligated TNFR1, TRADD further recruits the adapter protein TRAF2 via its N‐terminal TRAF‐binding domain SIGNOR-245029 SIGNOR-MacroPol Macrophage: Polarization and myogenesis TNFRSF1A protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 11502070 YES lperfetto The death domain of tnfrsf1a provides a novel molecular interface that interacts specifically with the death domain of tradd. SIGNOR-109719 SIGNOR-MacroPol Macrophage: Polarization and myogenesis TNFRSF1A protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 BTO:0000007 7758105 YES lperfetto We have identified a novel 34 kda protein, designated tradd, that specifically interacts with an intracellular domain of tnfr1 tradd interacts with the death domain of tnfrsf1a to initiate distinct signaling cascades for two of the most important biological activities of tnf, nf-kb activation and programmed cell death tradd, a novel protein that specifically interacts with the death domain of tnfr1 and activates signaling pathways for both of these activities when overexpressed. SIGNOR-32739 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL10RA protein Q13651 UNIPROT JAK1 protein P23458 UNIPROT up-regulates activity 9606 BTO:0000801 26260587 YES IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes. SIGNOR-253589 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL10RA protein Q13651 UNIPROT JAK1 protein P23458 UNIPROT up-regulates activity binding 9606 BTO:0000801;BTO:0000776 10347215 YES miannu Specifically, il-10 effects the activation of jak1 (associated with the il-10 receptor alpha Chain) and tyk2 (associated with the il-10 receptor beta Chain) and induces the activation of stat1, stat3, and, in some cells, stat5. SIGNOR-68010 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL10RA protein Q13651 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 26260587 YES lperfetto IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes. SIGNOR-249545 SIGNOR-MacroPol Macrophage: Polarization and myogenesis TGFBR1 protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser423 SPSIRCSsVS 10090 BTO:0005493;BTO:0000165 19458083 YES lperfetto A major event leading to smad3 activation is the tgf-beta-induced, tbetari-mediated phosphorylation at two c-terminal serine residues, ser-423 and ser-425, which triggers dissociation of smad3 from its receptors to form a complex with smad4 and accumulate in the nucleus SIGNOR-235385 SIGNOR-MacroPol Macrophage: Polarization and myogenesis TGFBR1 protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser425 SIRCSSVs 10090 BTO:0005493;BTO:0000165 19458083 YES lperfetto A major event leading to Smad3 activation is the TGF-beta-induced, TbetaRI-mediated phosphorylation at two C-terminal serine residues, Ser-423 and Ser-425, which triggers dissociation of Smad3 from its receptors to form a complex with Smad4 and accumulate in the nucleus SIGNOR-235380 SIGNOR-MacroPol Macrophage: Polarization and myogenesis TGFBR1 protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation 9606 19701891 YES miannu The binding of TGF‐β1 to its receptor complex activates the intracellular kinase domain of TGF‐βRII, which leads to the phosphorylation and activation of Smad2, Smad3 and Smad4 as well as non‐Smad proteins (Smad‐independent pathway) SIGNOR-254361 SIGNOR-MacroPol Macrophage: Polarization and myogenesis TGFBR1 protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 10973958 YES lperfetto The pathway restricted (r)Smads (e.g. Smad1, 2, 3, and 5) are serine/threonine kinase activated proteins that interact in an unphosphorylated state with a TGF-b superfamily receptor. Upon ligand binding they are phosphorylated by the receptor and released. SIGNOR-249549 SIGNOR-MacroPol Macrophage: Polarization and myogenesis TGFBR1 protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation Ser465 SPSVRCSsMS 9534 BTO:0001538 9346908 YES lperfetto Recently, it was demonstrated that Smad2 interacts transiently with and is a direct substrate of the transforming growth factor-_ (TGF-_) type I receptor, T_RI. Phosphorylation sites on smad2 were localized to a carboxyl-terminal fragment containing three serine residues at positions 464, 465, and 467. In this report, we show that T_RI specifically phosphorylates Smad2 on serines 465 and 467.These results indicate that receptor-dependent phosphorylation of Smad2 on serines 465 and 467 is required in mammalian cells to permit association with Smad4 and to propagate TGF-_ signals. SIGNOR-236107 SIGNOR-MacroPol Macrophage: Polarization and myogenesis TGFBR1 protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation Ser467 SVRCSSMs 9534 9346908 YES lperfetto Recently, it was demonstrated that Smad2 interacts transiently with and is a direct substrate of the transforming growth factor-beta (TGF-beta) type I receptor, TbetaRI. Phosphorylation sites on Smad2 were localized to a carboxyl-terminal fragment containing three serine residues at positions 464, 465, and 467. These results indicate that receptor-dependent phosphorylation of Smad2 on serines 465 and 467 is required in mammalian cells to permit association with Smad4 and to propagate TGF-_ signals. SIGNOR-235995 SIGNOR-MacroPol Macrophage: Polarization and myogenesis STAT3 protein P40763 UNIPROT SOCS3 protein O14543 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11159537 NO miannu STAT3-mediated constitutive expression of SOCS-3 in cutaneous T-cell lymphoma. SIGNOR-253050 SIGNOR-MacroPol Macrophage: Polarization and myogenesis STAT3 protein P40763 UNIPROT SOCS3 protein O14543 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12565872 YES We also found that the wild type SOCS-3 promoter construct has significantly greater activity in non-small-cell lung cancer cell lines than in normal cells in accordance with STAT3 disregulation in these cells SIGNOR-253583 SIGNOR-MacroPol Macrophage: Polarization and myogenesis STAT3 protein P40763 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 10347215 NO lperfetto The data presented this far show that the JAK-STAT signaling pathway and specifically Stat3 and Jak1 are required for induction of IL-10-dependent anti-inflammatory and developmental responses in macrophages. SIGNOR-249547 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL4 protein P05112 UNIPROT IL4R protein P24394 UNIPROT up-regulates activity binding 9606 BTO:0000801 18852293 YES lperfetto IL-4 signals through the type I (IL-4Ralpha/common gamma-chain [gammac]) and the type II (IL-4Ralpha/-13Ralpha1) IL-4 receptors, whereas IL-13 utilizes only the type II receptor. SIGNOR-249527 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL4 protein P05112 UNIPROT IL4R protein P24394 UNIPROT up-regulates binding -1 10219247 YES gcesareni Nterleukin-4 (il-4) is a principal regulatory cytokine during an immune response and a crucial determinant for allergy and asthma. Il-4 binds with high affinity and specificity to the ectodomain of the il-4 receptor alpha chain (il4-bp). SIGNOR-67217 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL4 protein P05112 UNIPROT IL4R protein P24394 UNIPROT up-regulates binding 9606 12704343 YES milica IL-4R Is a 140-kd protein that binds il-4 with high affinity SIGNOR-100762 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IRAK1 protein P51617 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation Thr209 LCEISRGtHNFSEEL 9606 BTO:0000007 14625308 YES lperfetto Sequential autophosphorylation steps in the interleukin-1 receptor-associated kinase-1 regulate its availability as an adapter in interleukin-1 signalingthis identifies irak-1 as a novel type of adapter protein, which employs its own kinase activity to introduce negative charges adjacent to the protein interaction domain, which anchors irak-1 at the active receptor complex. Thus, irak-1 regulates its own availability as an adapter molecule by sequential autophosphorylation SIGNOR-119212 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IRAK1 protein P51617 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation Thr387 RTQTVRGtLAYLPEE 9606 14625308 YES lperfetto Sequential autophosphorylation steps in the interleukin-1 receptor-associated kinase-1 regulate its availability as an adapter in interleukin-1 signalingthis identifies irak-1 as a novel type of adapter protein, which employs its own kinase activity to introduce negative charges adjacent to the protein interaction domain, which anchors irak-1 at the active receptor complex. Thus, irak-1 regulates its own availability as an adapter molecule by sequential autophosphorylation. SIGNOR-119216 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IRAK1 protein P51617 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation Ser376 GSSPSQSsMVARTQT -1 11960013 YES In vitro the IRAK-1 activation loop is a good substrate for IRAK-4, and that T387 and S376 are the main sites of phosphorylation by both IRAK-1 and IRAK-4. SIGNOR-251326 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IRAK1 protein P51617 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation Thr66 CERSGQRtASVLWPW 9534 BTO:0001538 12138165 YES T66E mutations interfered with the ability of IRAK to autophosphorylate. Thr-66 mutations abolished the capacity of IRAK to dimerize. SIGNOR-251327 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IRAK1 protein P51617 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation Thr387 RTQTVRGtLAYLPEE -1 11960013 YES In vitro the IRAK-1 activation loop is a good substrate for IRAK-4, and that T387 and S376 are the main sites of phosphorylation by both IRAK-1 and IRAK-4. SIGNOR-251330 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IRAK1 protein P51617 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 15465816 YES gcesareni Irak1 can directly use stat3 as a substrate and cause stat3 serine 727 phosphorylation. SIGNOR-129685 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL6R protein P08887 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 23663276 YES milica In classical il-6 signaling, the cytokine first binds to the membrane-bound il-6 receptor (il-6r;cd126) that is induced to associate with a homodimer of gp130 which then transmits the intracellular signal. SIGNOR-202033 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL6R protein P08887 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 BTO:0000785 11238858 YES gcesareni Part of the receptor for interleukin 6. Binds to il6 with low affinity, but does not transduce a signal. Signal activation necessitate an association with il6st. Activation may lead to the regulation of the immune response, acute-phase reactions and hematopoiesis. SIGNOR-105504 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL6R protein P08887 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation 9606 23869758 YES miannu On binding of IL-6 to its receptor IL-6R, JAK2 is phosphorylated, then STAT3 is phosphorylated by JAK2 SIGNOR-254405 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL6ST protein P40189 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity phosphorylation Ser661 NVPDPSKsHIAQWSP -1 8511589 YES lperfetto The biological functions of interleukin-6 (IL-6) are mediated through a signal-transducing component of the IL-6 receptor, gp130, which is associated with the ligand-occupied IL-6 receptor (IL-6R) protein. Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130. Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein. Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130. SIGNOR-238625 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL6ST protein P40189 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity phosphorylation Ser659 WPNVPDPsKSHIAQW -1 8511589 YES lperfetto The biological functions of interleukin-6 (IL-6) are mediated through a signal-transducing component of the IL-6 receptor, gp130, which is associated with the ligand-occupied IL-6 receptor (IL-6R) protein. Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130. Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein. Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130. SIGNOR-238621 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL6ST protein P40189 UNIPROT JAK1 protein P23458 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 23663276 YES milica Il-6 family members typically signal through the common gp130 receptor, with the janus kinase/signal transducer and activator of transcription (jak/stat) pathway being the major intracellular mediator of their effects. SIGNOR-202036 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL6ST protein P40189 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 24710148 YES milica The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3). SIGNOR-204841 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL6ST protein P40189 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 9716487 YES lperfetto All IL-6-type cytokines recruit gp130to their receptot complexes They either signal via gp130 alone [8] or in combination with LIFR [9] or the recently cloned OSMR [10], which are all able to activate Jaks proteins. Two tyrosine residues at the corresponding positions of Jak2 (tyrosine-1007 and tyrosine-1008) were found to be phosphorylated, and a single mutation of tyrosine-1007 eliminated essentially all tyrosine kinase activity [59]. SIGNOR-238630 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL6ST protein P40189 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1008 LPQDKEYyKVKEPGE 9606 9716487 YES lperfetto All IL-6-type cytokines recruit gp130to their receptot complexes They either signal via gp130 alone [8] or in combination with LIFR [9] or the recently cloned OSMR [10], which are all able to activate Jaks proteins. Two tyrosine residues at the corresponding positions of Jak2 (tyrosine-1007 and tyrosine-1008) were found to be phosphorylated, and a single mutation of tyrosine-1007 eliminated essentially all tyrosine kinase activity [59]. SIGNOR-238634 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL13 protein P35225 UNIPROT IL4R protein P24394 UNIPROT up-regulates binding 9606 12704343 YES milica Both il-4 and il-13 use the IL-4R Chain as a component of their receptors. SIGNOR-100753 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL4R protein P24394 UNIPROT JAK1 protein P23458 UNIPROT up-regulates 9606 7538655 NO lperfetto We demonstrate that il4r triggering induced the tyrosine phosphorylation of jak3 SIGNOR-34756 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL4R protein P24394 UNIPROT JAK1 protein P23458 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 23124025 YES lperfetto Although the receptor-associated tyrosine kinases Jak2 and Tyk2 are activated after the recruitment of IL-13 to its receptor (containing IL-4R and IL-13R1), IL-4 stimulates Jak1 activation. SIGNOR-249529 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL4R protein P24394 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 YES milica IL-4Rα, γc, and IL-13Rα1 all contain proline-rich box-1 regions that bind jak1, jak3, and tyk2, respectively. Il-4 uses the type ii receptor, and IL-13R1 Binds tyk2. Il-13 results in activation of jak1 and tyk2 in hematopoietic and nonhematopoietic cells. SIGNOR-100774 SIGNOR-MacroPol Macrophage: Polarization and myogenesis IL4R protein P24394 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 18852293 YES lperfetto Downstream intracellular signaling from the IL-4IL-4Rc complex involves activation of the Jak1 and Jak3 kinases, phosphorylation of the Stat6 transcription factor, and activation of the insulin receptor substrate (IRS)-2 and Dok2-signaling intermediates. IL-13 initially binds to IL-13R1 with intermediate affinity, and then heterodimerizes with IL-4R. The IL-13IL-13R1IL-4R complex activates the Tyk2, Jak2, and Jak1 kinases and Stat6. SIGNOR-249530 SIGNOR-MacroTNFA Macrophage: TNF alpha NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCL2 protein P13500 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000801 20086235 NO Both NF-κBs bind to a conserved DNA motif (80) that is found in numerous IL-1–responsive genes, in particular the ones encoding IκBα (81), IL-6 (82), IL-8 (18, 83,84), monocyte chemoattractant protein 1 (MCP1) (28), and cyclooxygenase 2 (COX2) SIGNOR-254509 SIGNOR-MacroTNFA Macrophage: TNF alpha NfKb-p65/p50 complex SIGNOR-C13 SIGNOR M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 9606 30060484 NO miannu The bacterial endotoxin LPS is a known agonist of TLR2 that activates the expression of proinflammatory cytokines and the phosphorylation of MAPKs and NFκB [49]. In addition, the activation of the MAPK and NFκB signaling cascades drive inflammation and macrophage polarization.  SIGNOR-249519 SIGNOR-MacroTNFA Macrophage: TNF alpha NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 20457564 NO gcesareni The nuclear factor NF-kappaB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-kappaB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules. SIGNOR-245039 SIGNOR-MacroTNFA Macrophage: TNF alpha IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 9346241 YES lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-216385 SIGNOR-MacroTNFA Macrophage: TNF alpha IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 9346241 YES lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-216389 SIGNOR-MacroTNFA Macrophage: TNF alpha IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation 9606 21232017 YES lperfetto Tak1 become activated and then phosphorilates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation SIGNOR-216396 SIGNOR-MacroTNFA Macrophage: TNF alpha IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 BTO:0000567 9346241 YES lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-209773 SIGNOR-MacroTNFA Macrophage: TNF alpha IKK-complex complex SIGNOR-C14 SIGNOR IKK-complex complex SIGNOR-C14 SIGNOR down-regulates phosphorylation 9606 10195894 YES lperfetto Once activated, ikkbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased ikk activity and may prevent prolonged activation of the inflammatory response SIGNOR-216373 SIGNOR-MacroTNFA Macrophage: TNF alpha IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 BTO:0000007 19609947 YES lperfetto Our data suggest that the stimulation of nfkb by akt is dependent on the phosphorylation of p65 at s534, mediated by ikk (ikb kinase) alfa and beta. SIGNOR-216365 SIGNOR-MacroTNFA Macrophage: TNF alpha IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 15489227 YES lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. SIGNOR-216341 SIGNOR-MacroTNFA Macrophage: TNF alpha TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT up-regulates activity binding 9606 11502070 YES lperfetto Binding of tnf to the extracellular domain of tnfrsf1a leads to homotrimerization. SIGNOR-109716 SIGNOR-MacroTNFA Macrophage: TNF alpha TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT up-regulates activity binding 9606 23070005 YES miannu For TNFR1, the cytokine TNFα binds to the receptor and triggers its trimerization, which leads to the assembly of the receptor complex and initiation of signaling. SIGNOR-199091 SIGNOR-MacroTNFA Macrophage: TNF alpha TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT up-regulates activity binding 9606 21133840 YES simone vumbaca TNF alpha and IFN gamma exhibit a cross-talk at the level of TNFR1 to induce activation of macrophages SIGNOR-256025 SIGNOR-MacroTNFA Macrophage: TNF alpha TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 10090 BTO:0002572;BTO:0000801 21232017 YES gcesareni Rip1 is known to directly interact with traf2 SIGNOR-245032 SIGNOR-MacroTNFA Macrophage: TNF alpha TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination Lys377 NEPSLQSkLQDEANY 9606 BTO:0000007 8702708 YES lperfetto Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2. SIGNOR-42984 SIGNOR-MacroTNFA Macrophage: TNF alpha RIPK1 protein Q13546 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 21133840 YES simone vumbaca RIP-1 recruitment of MEKK-3 and transforming growth factor-beta (TGFbeta)-activated kinase (TAK1) subsequently activates the IKK (inhibitor of Œ∫B kinase) complex SIGNOR-256022 SIGNOR-MacroTNFA Macrophage: TNF alpha MAP3K7 protein O43318 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates activity phosphorylation 9606 21133840 YES miannu RIP-1 recruitment of MEKK-3 and transforming growth factor-beta (TGFbeta)-activated kinase (TAK1) subsequently activates the IKK (inhibitor of Œ∫B kinase) complex SIGNOR-256024 SIGNOR-MacroTNFA Macrophage: TNF alpha TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 9606 BTO:0000007 27383048 YES miannu Upon stimulation with TNFα, TNFR1 recruits TRADD, which provides a scaffold for the assembly of complex I at the plasma membrane by binding with RIP1, TRAF2 and cIAP. SIGNOR-42980 SIGNOR-MacroTNFA Macrophage: TNF alpha TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 10090 14585074 YES lperfetto Tradd mediates recruitment of the traf2 adaptor protein SIGNOR-118770 SIGNOR-MacroTNFA Macrophage: TNF alpha TNFRSF1A protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 11502070 YES lperfetto The death domain of tnfrsf1a provides a novel molecular interface that interacts specifically with the death domain of tradd. SIGNOR-109719 SIGNOR-MacroTNFA Macrophage: TNF alpha TNFRSF1A protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 BTO:0000007 7758105 YES lperfetto We have identified a novel 34 kda protein, designated tradd, that specifically interacts with an intracellular domain of tnfr1 tradd interacts with the death domain of tnfrsf1a to initiate distinct signaling cascades for two of the most important biological activities of tnf, nf-kb activation and programmed cell death tradd, a novel protein that specifically interacts with the death domain of tnfr1 and activates signaling pathways for both of these activities when overexpressed. SIGNOR-32739 SIGNOR-MacroTNFA Macrophage: TNF alpha NFKBIA protein P25963 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 1340770 YES lperfetto Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b SIGNOR-217394 SIGNOR-MacroTNFA Macrophage: TNF alpha NFKBIA protein P25963 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 9914500 YES lperfetto In nonstimulated cells, nf-kappab is present in the cytosol where it is complexed to its inhibitor ikappab however, we found that only one of the activities, namely the ikk1/2 complex, exists as a pre-assembled kinase-substrate complex in which the ikks are directly or indirectly associated with several nf-kappab-related and ikappab-related proteins: rela, relb, crel, p100, p105, ikappa balpha, ikappa bbeta and ikappa bepsilon. SIGNOR-64092 SIGNOR-MacroTNFATR Macrophage: TNF alpha transcriptional regulation A9/b1 integrin complex SIGNOR-C166 SIGNOR TNF protein P01375 UNIPROT up-regulates quantity by expression 9606 24241034 NO lperfetto Importantly, autocrine and paracrine interactions of alpha9beta1 integrin and tenascin-C induced the expression of MMPs and IL-6 in synovial fibroblasts, as well as TNF-alpha± and IL-1beta in synovial macrophages. SIGNOR-253315 SIGNOR-MacroTNFATR Macrophage: TNF alpha transcriptional regulation KLF4 protein O43474 UNIPROT TNF protein P01375 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000801 22378047 NO miannu KLF4 cooperates with Stat6 to induce M2 genes (Arg-1, Mrc1, Fizz1, PPARγ) and inhibit M1 genes (TNFa, Cox-2, CCL5, iNOS) via sequestration of coactivators required for NF-κB activation. SIGNOR-254520 SIGNOR-MacroTNFATR Macrophage: TNF alpha transcriptional regulation IRF5 protein Q13568 UNIPROT TNF protein P01375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21240265 NO miannu Among the genes with differences in expression in the M1 and M2 subsets are those regulated by IRF5, including IL12A, IL12B, IL23A, IL1B, TNF, CCL3(encoding MIP-1Œ±), RANTES, CD1A, CD40, CD86 and CCR7 SIGNOR-254518 SIGNOR-MacroTNFATR Macrophage: TNF alpha transcriptional regulation STAT6 protein P42226 UNIPROT KLF4 protein O43474 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25934862 NO miannu IL-4-induced macrophage polarization involves induction of STAT6 and KLF4 that induce each other and promote M2 polarization. SIGNOR-254519 SIGNOR-MastFCERI Mast cell: FCERI Degranulation phenotype SIGNOR-PH92 SIGNOR IL6 protein P05231 UNIPROT up-regulates quantity 9606 BTO:0000830 24232182 NO apalma Particularly, damage-activated mast cells almost instantly begin to secrete TNFa, histamine and tryptase and then initiate the de novo synthesis of other cytokines, such as interleukin (IL)6 SIGNOR-255349 SIGNOR-MastFCERI Mast cell: FCERI Degranulation phenotype SIGNOR-PH92 SIGNOR IL5 protein P05113 UNIPROT up-regulates quantity 9606 BTO:0000830 17259966 NO apalma The array of mediators released by human mast cells is enormous and explains how mast cells can be involved in so many different physiological and pathophysiological functions. Of particular relevance [...] cytokines, such as IL-3 -basophil recruitment and activation-, IL-5 -eosinophil recruitment and activation- and IL-13 -induction of IgE synthesis by B cells. SIGNOR-255346 SIGNOR-MastFCERI Mast cell: FCERI Degranulation phenotype SIGNOR-PH92 SIGNOR TNF protein P01375 UNIPROT up-regulates quantity 9606 BTO:0000830 24232182 NO apalma Particularly, damage-activated mast cells almost instantly begin to secrete TNFa, histamine and tryptase and then initiate the de novo synthesis of other cytokines, such as interleukin (IL)6 SIGNOR-255347 SIGNOR-MastFCERI Mast cell: FCERI FCER1G/FCER1G complex SIGNOR-C199 SIGNOR FCER1 complex SIGNOR-C200 SIGNOR form complex binding 9606 BTO:0000830 16470226 YES Alessandro Palma FcepsilonRI is a tetrameric receptor that comprises an alpha-chain, which is responsible for binding IgE, as well as a beta-chain and a disulphide-linked gamma-chain homo dimer, which are responsible for initiating signalling. SIGNOR-254962 SIGNOR-MastFCERI Mast cell: FCERI FCER1 complex SIGNOR-C200 SIGNOR SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR up-regulates 9606 BTO:0000830 16470226 NO Alessandro Palma It is clear that these initial signalling events involve coalescence of the aggregated receptors with specialized microdomains of the plasma membrane known as lipid rafts9, activation of SRC-family kinases and, subsequently, tyrosine phosphorylation of the receptor subunits SIGNOR-254963 SIGNOR-MastFCERI Mast cell: FCERI FCER1 complex SIGNOR-C200 SIGNOR SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR up-regulates 9606 BTO:0000830 16470226 NO Alessandro Palma It is clear that these initial signalling events involve coalescence of the aggregated receptors with specialized microdomains of the plasma membrane known as lipid rafts9, activation of SRC-family kinases and, subsequently, tyrosine phosphorylation of the receptor subunits SIGNOR-254957 SIGNOR-MastFCERI Mast cell: FCERI FCER1 complex SIGNOR-C200 SIGNOR SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR up-regulates 9606 BTO:0000830 16470226 NO Alessandro Palma It is clear that these initial signalling events involve coalescence of the aggregated receptors with specialized microdomains of the plasma membrane known as lipid rafts9, activation of SRC-family kinases and, subsequently, tyrosine phosphorylation of the receptor subunits SIGNOR-254955 SIGNOR-MastFCERI Mast cell: FCERI SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR Degranulation phenotype SIGNOR-PH92 SIGNOR up-regulates 9606 16470226 NO Alessandro Palma So, the association of aggregated FcεRI with the preferentially activated LYN in lipid rafts might be sufficient to shift the equilibrium of FcεRI from a nonphosphorylated state to a phosphorylated state, thereby initiating FcεRI-mediated degranulation SIGNOR-254956 SIGNOR-MastFCERI Mast cell: FCERI FCER1A protein P12319 UNIPROT FCER1 complex SIGNOR-C200 SIGNOR form complex binding 9606 BTO:0000830 16470226 YES Alessandro Palma FcepsilonRI is a tetrameric receptor that comprises an alpha-chain, which is responsible for binding IgE, as well as a beta-chain and a disulphide-linked gamma-chain homo dimer, which are responsible for initiating signalling. SIGNOR-254959 SIGNOR-MastFCERI Mast cell: FCERI FCER1G protein P30273 UNIPROT FCER1G/FCER1G complex SIGNOR-C199 SIGNOR form complex binding 9606 BTO:0000830 16470226 YES Alessandro Palma FcepsilonRI is a tetrameric receptor that comprises an alpha-chain, which is responsible for binding IgE, as well as a beta-chain and a disulphide-linked gamma-chain homo dimer, which are responsible for initiating signalling. SIGNOR-254961 SIGNOR-MastFCERI Mast cell: FCERI MS4A2 protein Q01362 UNIPROT FCER1 complex SIGNOR-C200 SIGNOR form complex binding 9606 BTO:0000830 16470226 YES Alessandro Palma FcepsilonRI is a tetrameric receptor that comprises an alpha-chain, which is responsible for binding IgE, as well as a beta-chain and a disulphide-linked gamma-chain homo dimer, which are responsible for initiating signalling. SIGNOR-254960 SIGNOR-MastSCF Mast cell: SCF PI3K complex SIGNOR-C156 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000830 15526160 YES miannu C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. SIGNOR-254951 SIGNOR-MastSCF Mast cell: SCF PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15526160 YES miannu C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. SIGNOR-254950 SIGNOR-MastSCF Mast cell: SCF ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000830 15526160 NO Numerous studies have implicated the critical importance of the Ras/Erk pathway in cell division and survival SIGNOR-254948 SIGNOR-MastSCF Mast cell: SCF AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000830 15526160 NO miannu c-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. SIGNOR-254952 SIGNOR-MastSCF Mast cell: SCF SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR Chemotaxis phenotype SIGNOR-PH93 SIGNOR up-regulates 9606 15526160 NO apalma The SFK family of tyrosine kinases is named after its prototypic family member c-Src. SCF-induced chemotaxis of Mo7 cells was dependent on SFK activity SIGNOR-254996 SIGNOR-MastSCF Mast cell: SCF STAT5A protein P42229 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000830 20535135 NO miannu Specifically, SCF-induced activation of JAK2 in human mast cells has been shown to activate STAT5 and STAT6. STAT5 contributes to mast cell homeostasis, by mediating proliferation, survival, and mediator release. SIGNOR-256233 SIGNOR-MastSCF Mast cell: SCF JAK2 protein O60674 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 4932 9575217 YES gcesareni Our mutational analysis suggests that the Stat5 SH2 domain is essential for the interaction with Jak2 and that the kinase domain of Jak2 is sufficient for Jak2-Stat5 interaction. Therefore, the Jak kinase domain may be all that is needed to cause Stat phosphorylation in situations where receptor docking is dispensable. [...] Most obviously, mutation of Tyr694 (Stat5a) or Tyr699 (Stat5b) to phenylalanine abolishes phosphorylation SIGNOR-56827 SIGNOR-MastSCF Mast cell: SCF BAD protein Q92934 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR down-regulates 9606 BTO:0000830 15526160 NO miannu C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. SIGNOR-254953 SIGNOR-MastSCF Mast cell: SCF KITLG protein P21583 UNIPROT KIT protein P10721 UNIPROT up-regulates activity binding 9606 17259966 YES miannu The most relevant and still unique mast-cell growth factor is SCF, which is the ligand of KIT, a receptor with tyrosine-kinase activity that is expressed on the surface of all human and murine mast cells SIGNOR-254946 SIGNOR-MastSCF Mast cell: SCF KIT protein P10721 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity binding 9606 15526160 YES miannu C-Kit stimulates rapid and transient tyrosine phosphorylation of JAK2. JAK2 was found to be constitutively associated with c-Kit, with increased association after ligand stimulation of c-Kit SIGNOR-254954 SIGNOR-MastSCF Mast cell: SCF KIT protein P10721 UNIPROT SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR up-regulates phosphorylation 9606 15526160 YES apalma Binding of SCF to c-Kit leads to a rapid increase in SFK kinase activity SIGNOR-254995 SIGNOR-MastSCF Mast cell: SCF KIT protein P10721 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 BTO:0000830 15526160 NO miannu A number of studies have demonstrated the ability of SCF to activate the Ras-Erk pathway. The adapter protein Grb2 can directly associate with phosphorylated Y703 and Y936 in c-Kit SIGNOR-254947 SIGNOR-MastSCF Mast cell: SCF KIT protein P10721 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000830 15526160 YES miannu Activation of PI3-kinase by c-Kit has been linked to mitogenesis, differentiation, survival, adhesion, secretion and actin cytoskeletal reorganization. In c-Kit, Y721 has been found to directly interact with PI3-kinase SIGNOR-254949 SIGNOR-MB Myofiber: BMP FOXO proteinfamily SIGNOR-PF27 SIGNOR MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000222 18854138 NO gcesareni Our cell-based assays and in vitro studies reveal a tight codependent partnership between foxo3 and pax3/7 to coordinately recruit rna polymerase ii and form a preinitiation complex (pic) to activate myod transcription in myoblasts. SIGNOR-252937 SIGNOR-MB Myofiber: BMP FOXO proteinfamily SIGNOR-PF27 SIGNOR FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 15109499 YES The activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1 induction. IGF-1 treatment or AKT overexpression inhibits Foxo and atrogin-1 expression. SIGNOR-252926 SIGNOR-MB Myofiber: BMP FOXO proteinfamily SIGNOR-PF27 SIGNOR FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15109499 YES Constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers SIGNOR-252929 SIGNOR-MB Myofiber: BMP FOXO proteinfamily SIGNOR-PF27 SIGNOR Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 BTO:0001103 15109499 NO gcesareni Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. SIGNOR-252932 SIGNOR-MB Myofiber: BMP mTORC1 complex SIGNOR-C3 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 15829723 NO apalma Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K (47). This latter event has great potential importance for the promotion of muscle growth by the IGF-I/Akt/mTOR pathway, because p70S6k is a potent stimulator of protein synthesis that can be activated by increases in muscle contraction SIGNOR-256064 SIGNOR-MB Myofiber: BMP SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR form complex binding 9606 20957627 YES lperfetto Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus. SIGNOR-255838 SIGNOR-MB Myofiber: BMP SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR FBXO30 protein Q8TB52 UNIPROT down-regulates 10090 BTO:0000887 24076600 NO BMP-Smad1/5/8 signaling negatively regulates a gene (Fbxo30) that encodes a ubiquitin ligase required for muscle loss, which we named muscle ubiquitin ligase of the SCF complex in atrophy-1 (MUSA1) SIGNOR-256488 SIGNOR-MB Myofiber: BMP SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 10090 BTO:0000887 24145169 NO The BMP pathway is a positive regulator of muscle mass. Increasing the expression of BMP7 or the activity of BMP receptors in muscles induced hypertrophy that was dependent on Smad1/5-mediated activation of mTOR signaling SIGNOR-256487 SIGNOR-MB Myofiber: BMP NOG protein Q13253 UNIPROT BMP7 protein P18075 UNIPROT down-regulates activity binding -1 12478285 YES We report the crystal structure of the antagonist Noggin bound to BMP-7, which shows that Noggin inhibits BMP signalling by blocking the molecular interfaces of the binding epitopes for both type I and type II receptors. SIGNOR-256484 SIGNOR-MB Myofiber: BMP NOG protein Q13253 UNIPROT GDF5 protein P43026 UNIPROT down-regulates activity binding 9606 19956691 YES Regulation miannu We identified two mutations (N445K,T) in patients with multiple synostosis syndrome (SYM1) in the BMP–related ligand GDF5. Residue N445, situated within overlapping receptor and antagonist interfaces, is highly conserved among the BMP family with the exception of BMP9 and BMP10, in which it is substituted with lysine. Like the mutant GDF5, both BMPs are insensitive to NOGGIN and show a high chondrogenic activity. SIGNOR-251865 SIGNOR-MB Myofiber: BMP BMPR1A protein P36894 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR form complex binding 9606 7791754 YES lperfetto Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors (br-ia and br-ib) and the bmp type ii receptor (br-ii). SIGNOR-255257 SIGNOR-MB Myofiber: BMP BMPR1B protein O00238 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR form complex binding 9606 7791754 YES lperfetto Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors (br-ia and br-ib) and the bmp type ii receptor (br-ii). SIGNOR-33431 SIGNOR-MB Myofiber: BMP GDF5 protein P43026 UNIPROT BMPR1B protein O00238 UNIPROT up-regulates activity binding 10090 15890363 YES In contrast to other members of the TGF-beta superfamily, GDF-5 shows a pronounced specificity in type I receptor interaction in cross-link experiments binding only to BMP receptor IB (BMPR-IB). In mice, deletion of either GDF-5 or BMPR-IB results in a similar phenotype, indicating that GDF-5 signaling is highly dependent on BMPR-IB. SIGNOR-256483 SIGNOR-MB Myofiber: BMP FBXO30 protein Q8TB52 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 BTO:0000887 24076600 NO gene (Fbxo30) that encodes a ubiquitin ligase required for muscle loss, which we named muscle ubiquitin ligase of the SCF complex in atrophy-1 (MUSA1) SIGNOR-256489 SIGNOR-MB Myofiber: BMP FBXO32 protein Q969P5 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 25096180 NO Muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx)/atrogin-1 were identified more than 10 years ago as two muscle-specific E3 ubiquitin ligases that are increased transcriptionally in skeletal muscle under atrophy-inducing conditions, making them excellent markers of muscle atrophy SIGNOR-252072 SIGNOR-MB Myofiber: BMP FBXO32 protein Q969P5 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates activity 10090 25549588 NO areggio Muscle-specific ubiq- uitin ligases, muscle-specific RING-finger 1 (MURF1; also known as TRIM63)12 and atrogin 1 (also known as MAFBX)8, are markedly induced in almost all types of atrophy. SIGNOR-254994 SIGNOR-MB Myofiber: BMP FBXO32 protein Q969P5 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 BTO:0001103 20871233 NO Atrogin-1, but not MuRF-1, was induced at both the gene and protein level as ApcMin/+ mice aged from 3 to 6 months of age, going from a pre-cachectic to a cachectic state. Atrogin-1 mRNA and protein levels were also elevated in ApcMin/+ mice when we over-expressed IL-6 in the circulation. SIGNOR-255343 SIGNOR-MB Myofiber: BMP BMP7 protein P18075 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates binding 9606 7644468 YES lperfetto In transfected cos-1 cells, osteogenic protein (op)-1/bmp-7, and less efficiently bmp-4, bound to bmpr-ii. Bmpr-ii bound ligands only weakly alone, but the binding was facilitated by the presence of previously identified type i receptors for bmps. Binding of op-1/bmp-7 to bmpr-ii was also observed in nontransfected cell lines. Moreover, a transcriptional activation signal was transduced by bmpr-ii in the presence of type i receptors after stimulation by op-1/bmp-7. SIGNOR-217520 SIGNOR-MB Myofiber: BMP HDAC1 protein Q13547 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity deacetylation 10090 BTO:0000887 24463822 YES Through the use of various pharmacological inhibitors to block HDAC activity, we demonstrate that class I HDACs are key regulators of FoxO and the muscle-atrophy program during both nutrient deprivation and skeletal muscle disuse. SIGNOR-256485 SIGNOR-MCMF Myofiber: Calcium-mediated fusion Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation 9606 21880741 YES miannu Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. SIGNOR-255463 SIGNOR-MCMF Myofiber: Calcium-mediated fusion calcium(2+) smallmolecule CHEBI:29108 ChEBI CAMK2D protein Q13557 UNIPROT up-regulates activity chemical activation 9606 19725819 YES areggio Upon binding of the Ca2+/calmodulin complex to the binding domain of CaMKII, it is activated via autophosphorylation, then remaining active independent of of Ca2+ levels. SIGNOR-255953 SIGNOR-MCMF Myofiber: Calcium-mediated fusion calcium(2+) smallmolecule CHEBI:29108 ChEBI Calcineurin complex SIGNOR-C155 SIGNOR up-regulates activity chemical activation 9606 21880741 YES miannu Except for nfat5, nfatc1c4 are activated upon a rise in intracellular ca2+, which stimulates the serine/threonine phosphatase activity of calcineurin the ca2+-calcineurin signal is the most important signal for regulating nfat activation, but the signal that leads to ca2+ influx during neural tube differentiation is still unclear. SIGNOR-255462 SIGNOR-MCMF Myofiber: Calcium-mediated fusion NFATC2 protein Q13469 UNIPROT MYOF protein Q9NZM1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 23612709 NO miannu Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin SIGNOR-255465 SIGNOR-MCMF Myofiber: Calcium-mediated fusion NFATC2 protein Q13469 UNIPROT IL4 protein P05112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 11956291 NO IRF4 synergizes with NFATc2 and the IL-4-inducing transcription factor, c-maf, to augment IL-4 promoter activity as well as to elicit significant levels of endogenous IL-4 production SIGNOR-254502 SIGNOR-MCMF Myofiber: Calcium-mediated fusion NFATC2 protein Q13469 UNIPROT IL4 protein P05112 UNIPROT up-regulates transcriptional regulation 9606 23612709 NO Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin SIGNOR-255460 SIGNOR-MCMF Myofiber: Calcium-mediated fusion IL4 protein P05112 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 10090 12757709 NO miannu These data demonstrate that following myotube formation, myotubes recruit myoblast fusion by secretion of IL-4, leading to muscle growth SIGNOR-255896 SIGNOR-MCMF Myofiber: Calcium-mediated fusion MYOF protein Q9NZM1 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 9606 23612709 NO Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin SIGNOR-255466 SIGNOR-MCMF Myofiber: Calcium-mediated fusion CAMK2D protein Q13557 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates 9606 19725819 NO areggio In response toincreases in intracellular Ca2+ levels, activated CaMKII translocates into the nucleus where it phosphorylates and deactivates HDAC4 which, as a result, dissociates from theDNA-binding domain of MEF2. This dissociation allows MEF2 to bind to its DNA-binding domain to activate transcription of the MEF2-dependent target gene products MyoD and myogenin SIGNOR-255956 SIGNOR-MCMF Myofiber: Calcium-mediated fusion CAMK2D protein Q13557 UNIPROT CAMK2D protein Q13557 UNIPROT up-regulates phosphorylation 9606 19725819 YES areggio Upon binding of the Ca2+/calmodulin complex to the binding domain of CaMKII, it is activated via autophosphorylation, then remaining active independent of of Ca2+ levels. SIGNOR-255954 SIGNOR-MCMF Myofiber: Calcium-mediated fusion CAMK2D protein Q13557 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 9606 19725819 NO areggio In the cytoplasm where the activated CaMKII localises it induces signalling pathways that are mainly involved in mitochondrial biogenesis and expression of contractile protein SIGNOR-255955 SIGNOR-MCMF Myofiber: Calcium-mediated fusion MEF2A protein Q02078 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 9606 19725819 NO areggio In response to increases in intracellular Ca2+ levels, activated CaMKII translocates into the nucleus where it phosphorylates and deactivates HDAC4 which, as a result, dissociates from theDNA-binding domain of MEF2. This dissociation allows MEF2 to bind to its DNA-binding domain to activate transcription of the MEF2-dependent target gene products MyoD and myogenin SIGNOR-255957 SIGNOR-MH Myofiber: hypertrophy_cAMP (R)-adrenaline smallmolecule CHEBI:28918 ChEBI ADRB2 protein P07550 UNIPROT up-regulates chemical activation 9606 22863277 YES gcesareni In contrast, stimulation of gs-coupled receptors by glucagon or epinephrine activates lats1/2 kinase activity, thereby inhibiting yap function. SIGNOR-198501 SIGNOR-MH Myofiber: hypertrophy_cAMP 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKACA protein P17612 UNIPROT up-regulates chemical activation 9606 BTO:0000007 22863277 YES milica The cAMP signaling cascade can activate protein kinase a (PKA) SIGNOR-198492 SIGNOR-MH Myofiber: hypertrophy_cAMP 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKACA protein P17612 UNIPROT up-regulates chemical activation 9606 16293724 YES gcesareni Pge2 receptors are coupled to the G protein Gs, which causes accumulation of cyclic adenosine monophosphate (cAMP) and activates protein kinase a (PKA), we confirmed that PGE2 treatment or transfection of cells with the active catalytic subunit of PKA also stimulated the activity of a cAMP-responsive-element driven reporter gene (CRE-luc). SIGNOR-141786 SIGNOR-MH Myofiber: hypertrophy_cAMP PPARGC1A protein Q9UBK2 UNIPROT IGF1 protein P05019 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 23217713 YES miannu PGC-1 alpha specifically induces IGF1 and represses myostatin, and expression of PGC-1a 4 in vitro and in vivo induces robust skeletal muscle hypertrophy SIGNOR-256152 SIGNOR-MH Myofiber: hypertrophy_cAMP PPARGC1A protein Q9UBK2 UNIPROT MSTN protein O14793 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 23217713 YES miannu PGC-1 alpha specifically induces IGF1 and represses myostatin, and expression of PGC-1a 4 in vitro and in vivo induces robust skeletal muscle hypertrophy SIGNOR-256151 SIGNOR-MH Myofiber: hypertrophy_cAMP ADRB2 protein P07550 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 14500986 YES We have found that signaling via the erythrocyte beta2-adrenergic receptor and heterotrimeric guanine nucleotide-binding protein (Galphas) regulated the entry of the human malaria parasite Plasmodium falciparum. SIGNOR-256149 SIGNOR-MH Myofiber: hypertrophy_cAMP CREB1 protein P16220 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 21902831 NO gcesareni Chen et al. showed that phosphorylated creb is present at high levels in cells of the dermomyotome that express pax3, myod and myf5 and that this phosphorylation is critical for the induction of these genes. SIGNOR-176536 SIGNOR-MH Myofiber: hypertrophy_cAMP CREB1 protein P16220 UNIPROT FST protein P19883 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 15130492 NO lperfetto MyoD, CREB, and NFAT Mediate the Transcriptional Activation of the Follistatin Promoter Induced by TSA SIGNOR-251714 SIGNOR-MH Myofiber: hypertrophy_cAMP CREB1 protein P16220 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11557984 YES CREB was found to induce expression of the gluconeogenic programme through the nuclear receptor coactivator PGC-1, which is shown here to be a direct target for CREB regulation in vivo SIGNOR-256150 SIGNOR-MH Myofiber: hypertrophy_cAMP PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 10116 BTO:0001009 8336722 YES gcesareni The degree of CREB phosphorylation, assessed with antiserum specific for CREB phosphorylated at Ser-133, correlated with the amount of PKA liberated. The time course of phosphorylation closely paralleled the nuclear entry of the catalytic subun SIGNOR-166342 SIGNOR-MH Myofiber: hypertrophy_cAMP PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000669 15568017 YES gcesareni Using a combination of in vitro explant assays, mutant analysis and gene delivery into mouse embryos cultured ex vivo, we demonstrate that adenylyl cyclase signalling via PKA and its target transcription factor CREB are required for WNT-directed myogenic gene expression. SIGNOR-131307 SIGNOR-MH Myofiber: hypertrophy_cAMP PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000742 15568017 YES gcesareni We demonstrate that adenylyl cyclase signalling via PKA and its target transcription factor CREB are required for Wnt-directed myogenic gene expression. SIGNOR-255799 SIGNOR-MH Myofiber: hypertrophy_cAMP PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001103 21902831 YES gcesareni Phosphorylation of CREB by PKA allows it to initiate the transcription of genes that contain a CRE element, two of which are PAX3 and MYF5. SIGNOR-176560 SIGNOR-MH Myofiber: hypertrophy_cAMP ADCY1 protein Q08828 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates chemical modification 9606 17251915 YES gcesareni Typically Gas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate many molecules, including phospholipases, ion channels and lipid kinases. SIGNOR-152546 SIGNOR-MH Myofiber: hypertrophy_cAMP ADCY1 protein Q08828 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates chemical modification 9606 22863277 YES milica To further explore the role of camp signaling in the hippo pathway, we treated cells with forskolin, an activator of adenylyl cyclase that results in cAMP production. SIGNOR-198486 SIGNOR-MH Myofiber: hypertrophy_cAMP MYOD1 protein P15172 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 NO lperfetto The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop-helix (bHLH) motif that mediates dimerization and dna binding. [...] myogenic bHLH proteins form heterodimers with ubiquitous bHLH proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. SIGNOR-37458 SIGNOR-MMDD Myogenesis modulation: DNA damage DNA_damage stimulus SIGNOR-ST1 SIGNOR ATM protein Q13315 UNIPROT up-regulates 9606 21034966 NO lperfetto the ATM-Chk2 and ATR-Chk1 pathways, which are activated by DNA double-strand breaks (DSBs) and single-stranded DNA respectively. SIGNOR-242612 SIGNOR-MMDD Myogenesis modulation: DNA damage DNA_damage stimulus SIGNOR-ST1 SIGNOR ATM protein Q13315 UNIPROT up-regulates activity 9606 BTO:0000007 12556884 NO miannu Cellular irradiation induces rapid intermolecular autophosphorylation of serine 1981 that causes dimer dissociation and initiates cellular ATM kinase activity. Most ATM molecules in the cell are rapidly phosphorylated on this site after doses of radiation as low as 0.5 Gy, and binding of a phosphospecific antibody is detectable after the introduction of only a few DNA double-strand breaks in the cell. Activation of the ATM kinase seems to be an initiating event in cellular responses to irradiation. SIGNOR-253376 SIGNOR-MMDD Myogenesis modulation: DNA damage ATM protein Q13315 UNIPROT ABL1 protein P00519 UNIPROT up-regulates phosphorylation Ser446 PYPGIDLsQVYELLE 9606 BTO:0000938 9168116 YES lperfetto Ataxia telangiectasia mutant protein activates c-abl tyrosine kinase in response to ionizing radiation. Atm kinase domain corrects this defect, as it phosphorylates the c-abl tyrosine kinase in vitro at ser 465, leading to the activation of c-abl. SIGNOR-48818 SIGNOR-MMDD Myogenesis modulation: DNA damage ATM protein Q13315 UNIPROT ABL1 protein P00519 UNIPROT up-regulates binding 9606 9168117 YES acerquone Our results demonstrate that the sh3 domain of c-abl interacts with a dpapnpphfp motif (residues 1,373-1,382) of atm.These findings indicate that atm is involved in the activation of c-abl by dna damag SIGNOR-48822 SIGNOR-MMDD Myogenesis modulation: DNA damage ABL1 protein P00519 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates activity phosphorylation Tyr30 FATTDDFyDDPCFDSP 9606 BTO:0000007 12415271 YES We have found that c-Abl can phosphorylate MyoD at a conserved N-terminal tyrosine (Tyr30) that is located within the transactivation domain. Mutation of Tyr30 to Phe does not interfere with the function of MyoD, but theTyr30Phe mutant becomes resistant to the inhibitory effect of DNA damage. SIGNOR-253055 SIGNOR-MMDD Myogenesis modulation: DNA damage MYOD1 protein P15172 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 NO lperfetto The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop-helix (bHLH) motif that mediates dimerization and dna binding. [...] myogenic bHLH proteins form heterodimers with ubiquitous bHLH proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. SIGNOR-37458 SIGNOR-MonoIL10TR Monocyte: IL10 transcriptional regulation PAMPs stimulus SIGNOR-ST11 SIGNOR TLR4 protein O00206 UNIPROT up-regulates activity 9606 BTO:0000801 19946286 NO lperfetto The lipopolysaccharide (LPS) of Gram negative bacteria is a wellknown inducer of the innate immune response1. Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common pattern in structurally diverse LPS molecules. SIGNOR-249516 SIGNOR-MonoIL10TR Monocyte: IL10 transcriptional regulation ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR IL10 protein P22301 UNIPROT up-regulates quantity 10090 BTO:0004732 26208884 NO The mitogen activated protein kinases ERK1/2 play an important role in response to toll like receptor (TLR) activation and cytokine production, including IL-10 and IL-12. SIGNOR-256080 SIGNOR-MonoIL10TR Monocyte: IL10 transcriptional regulation MYD88 protein Q99836 UNIPROT TRAF3 protein Q13114 UNIPROT up-regulates activity binding 10090 BTO:0000906 16306937 YES Using MyD88 as a prototypical adaptor, we identified TNF receptor-associated factor 3 (TRAF3) as a new component of TIR signalling complexes that is recruited along with TRAF6. SIGNOR-256079 SIGNOR-MonoIL10TR Monocyte: IL10 transcriptional regulation TLR4 protein O00206 UNIPROT MAP3K8 protein P41279 UNIPROT up-regulates activity 10090 16484370 NO Our findings indicate that the Tpl2/MEK/ERK signaling module is a master regulator of ERK-dependent gene expression downstream of TLRs in different hemopoietic cells SIGNOR-256083 SIGNOR-MonoIL10TR Monocyte: IL10 transcriptional regulation TLR4 protein O00206 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 10090 22664090 YES gcesareni To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-252067 SIGNOR-MonoIL10TR Monocyte: IL10 transcriptional regulation TLR4 protein O00206 UNIPROT MYD88 protein Q99836 UNIPROT up-regulates activity binding 10090 22664090 YES gcesareni To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-252065 SIGNOR-MonoIL10TR Monocyte: IL10 transcriptional regulation ATF1 protein P18846 UNIPROT IL10 protein P22301 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10540320 NO miannu Our data suggest that intracellular cAMP may directly affect expression of the immunoregulatory cytokine IL-10 in monocytic cells via activation of the eukaryotic transcription factors CREB-1 and ATF-1 and their binding to CRE1 and CRE4 in the upstream enhancer of the IL-10 promoter SIGNOR-254521 SIGNOR-MonoIL10TR Monocyte: IL10 transcriptional regulation CREB1 protein P16220 UNIPROT IL10 protein P22301 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10540320 NO miannu Our data suggest that intracellular cAMP may directly affect expression of the immunoregulatory cytokine IL-10 in monocytic cells via activation of the eukaryotic transcription factors CREB-1 and ATF-1 and their binding to CRE1 and CRE4 in the upstream enhancer of the IL-10 promoter SIGNOR-254522 SIGNOR-MonoIL10TR Monocyte: IL10 transcriptional regulation TRAF3 protein Q13114 UNIPROT IL10 protein P22301 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16306937 NO miannu TRAF3 is essential for the induction of type I interferons (IFN) and the anti-inflammatory cytokine interleukin-10 (IL-10), but is dispensable for expression of pro-inflammatory cytokines. SIGNOR-256077 SIGNOR-MonoIL10TR Monocyte: IL10 transcriptional regulation CEBPB protein P17676 UNIPROT IL10 protein P22301 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12493739 NO miannu The C/EBP5 motif, which is located between the TATA-box and the translation start point, is essential for the C/EBP-mediated constitutive and most of the cAMP-stimulated expression as its mutation nearly abolished IL-10 promoter activity. Our results suggest a dominant role of C/EBP transcription factors relative to CREB/ATF in tissue-specific and differentiation-dependent IL-10 transcription SIGNOR-254523 SIGNOR-MonoIL10TR Monocyte: IL10 transcriptional regulation MAP3K8 protein P41279 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 10090 BTO:0000776; BTO:0000801 16484370 NO Mitogen-activated protein 3 kinase Tpl2, levels of which are markedly reduced in nfkb1(-/-) cells, is required for extracellular signal-regulated kinase (ERK) activation in bone marrow-derived macrophages and B cells stimulated with diverse TLR ligands SIGNOR-256078 SIGNOR-MonoMAC Monocyte: Macrophage differentiation PI3K complex SIGNOR-C156 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 19436055 NO apalma Low pM concentrations of GM-CSF mediate βc Ser585 phosphorylation, leading to 14-3-3 binding, PI-3 kinase activation, and hemopoietic cell survival, whereas at concentrations of 10 pM or more, GM-CSF mediates βc Tyr577 phosphorylation, Shc recruitment, and PI-3 kinase activation, thereby promoting both survival and proliferation. SIGNOR-255576 SIGNOR-MonoMAC Monocyte: Macrophage differentiation PI3K complex SIGNOR-C156 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 19436055 NO apalma Low pM concentrations of GM-CSF mediate βc Ser585 phosphorylation, leading to 14-3-3 binding, PI-3 kinase activation, and hemopoietic cell survival, whereas at concentrations of 10 pM or more, GM-CSF mediates βc Tyr577 phosphorylation, Shc recruitment, and PI-3 kinase activation, thereby promoting both survival and proliferation. SIGNOR-255577 SIGNOR-MonoMAC Monocyte: Macrophage differentiation CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 BTO:0000876 BTO:0001103 19436055 NO apalma As a consequence of Jak2 activation and tyrosine phosphorylation of the cytoplasmic tail of beta-c, Src homology 2 and phosphotyrosine binding domain proteins are recruited to the active receptor and initiate the major tyrosine phosphorylation-dependent signaling pathways, including the Jak/signal transducer and activator of transcription, Ras/mitogen-activated protein kinase, and phosphatidylinositol 3 (PI-3) kinase pathways SIGNOR-255586 SIGNOR-MonoMAC Monocyte: Macrophage differentiation CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 19436055 YES miannu As a consequence of Jak2 activation and tyrosine phosphorylation of the cytoplasmic tail of Œ≤c, Src homology 2 and phosphotyrosine binding domain proteins are recruited to the active receptor and initiate the major tyrosine phosphorylation-dependent signaling pathways, including the Jak/signal transducer and activator of transcription, Ras/mitogen-activated protein kinase, and phosphatidylinositol 3 (PI-3) kinase pathways SIGNOR-255585 SIGNOR-MonoMAC Monocyte: Macrophage differentiation ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Macrophage_differentiation phenotype SIGNOR-PH99 SIGNOR up-regulates 9606 24890514 NO apalma The Erk1/2 pathway has a central role in CSF-1R-regulated myeloid differentiation. CSF-1 induces early (peaking at ‚àº5 min) and persistent (starting at 1 h) waves of MEK/Erk1/2 phosphorylation SIGNOR-255573 SIGNOR-MonoMAC Monocyte: Macrophage differentiation ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 11602185 NO apalma The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding. SIGNOR-255579 SIGNOR-MonoMAC Monocyte: Macrophage differentiation ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 11602185 NO apalma The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding. SIGNOR-255580 SIGNOR-MonoMAC Monocyte: Macrophage differentiation CSF1 protein P09603 UNIPROT CSF1R protein P07333 UNIPROT up-regulates activity binding 9606 BTO:0000876 BTO:0001103 24890514 YES apalma The CSF-1 receptor (CSF-1R) is activated by the homodimeric growth factors colony-stimulating factor-1 (CSF-1) and interleukin-34 (IL-34) SIGNOR-255568 SIGNOR-MonoMAC Monocyte: Macrophage differentiation STAT5A protein P42229 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 19436055 NO miannu The alternative survival and proliferation pathway triggered by higher concentrations of GM-CSF is dependent on the dodecamer assembly and involves the Jak/STAT, Ras/mitogen-activated protein kinase, and PI-3 kinase pathways SIGNOR-255578 SIGNOR-MonoMAC Monocyte: Macrophage differentiation SOCS1 protein O15524 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 24890514 NO apalma Socs1 associates with CSF-1R pTyr-697 and pTyr721 binding sites to inhibit proliferation by an unknown mechanism SIGNOR-255575 SIGNOR-MonoMAC Monocyte: Macrophage differentiation JAK2 protein O60674 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 4932 9575217 YES gcesareni Our mutational analysis suggests that the Stat5 SH2 domain is essential for the interaction with Jak2 and that the kinase domain of Jak2 is sufficient for Jak2-Stat5 interaction. Therefore, the Jak kinase domain may be all that is needed to cause Stat phosphorylation in situations where receptor docking is dispensable. [...] Most obviously, mutation of Tyr694 (Stat5a) or Tyr699 (Stat5b) to phenylalanine abolishes phosphorylation SIGNOR-56827 SIGNOR-MonoMAC Monocyte: Macrophage differentiation JAK2 protein O60674 UNIPROT CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000876 BTO:0001103 19436055 YES apalma The GM-CSF receptor does not have intrinsic tyrosine kinase activity, but associates with the tyrosine kinase Jak2 that is required for Œ≤c transphosphorylation and the initiation of signaling and biological activity SIGNOR-255584 SIGNOR-MonoMAC Monocyte: Macrophage differentiation CSF2 protein P04141 UNIPROT CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR up-regulates binding 9606 BTO:0000876 BTO:0001103 9680354 YES apalma GM-CSF elicits these diverse responses through the GM-CSF receptor (GMR). SIGNOR-255581 SIGNOR-MonoMAC Monocyte: Macrophage differentiation CSF1R protein P07333 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates 9606 24890514 YES apalma Studies with multipotent precursor cell lines (Fig. 4A) indicate that CSF-1R Tyr-807 and Tyr-721 promote macrophage differentiation via the PLC-Œ≥2 pathway SIGNOR-255570 SIGNOR-MonoMAC Monocyte: Macrophage differentiation CSF1R protein P07333 UNIPROT CSF1R protein P07333 UNIPROT up-regulates phosphorylation Tyr699 DPEGGVDyKNIHLEK 9606 15297464 YES lperfetto Csf-1r homodimerizes and autophosphorylates on six tyrosines in the cytoplasmic portion of the receptor. Tyr807 is located in the activation loop of the kinase domain (9) and its phosphorylation is important for kinase activity (10). The remaining tyrosines serve as binding sites for proteins containing src homology 2 (sh2) binding domains. Three sites are found in the ki: grb2/mona (tyr697) (11, 12), p85 subunit of phosphatidylinositol 3-kinase (tyr721) (13), and stat1 (tyr706) (14), the c-cbl binding site is in the cooh terminus (tyr974) (15, 16), and the src family kinase (sfk) binding site is in the jmd (y559) (17). These molecules further propagate the csf-1 signal through activation of ras/erk, phosphatidylinositol 3-kinase/akt, and stat proteins. SIGNOR-127536 SIGNOR-MonoMAC Monocyte: Macrophage differentiation CSF1R protein P07333 UNIPROT CSF1R protein P07333 UNIPROT up-regulates phosphorylation Tyr708 NIHLEKKyVRRDSGF 9606 BTO:0001271 15297464 YES lperfetto Csf-1r homodimerizes and autophosphorylates on six tyrosines in the cytoplasmic portion of the receptor. Tyr807 is located in the activation loop of the kinase domain (9) and its phosphorylation is important for kinase activity (10). The remaining tyrosines serve as binding sites for proteins containing src homology 2 (sh2) binding domains. Three sites are found in the ki: grb2/mona (tyr697) (11, 12), p85 subunit of phosphatidylinositol 3-kinase (tyr721) (13), and stat1 (tyr706) (14), the c-cbl binding site is in the cooh terminus (tyr974) (15, 16), and the src family kinase (sfk) binding site is in the jmd (y559) (17). These molecules further propagate the csf-1 signal through activation of ras/erk, phosphatidylinositol 3-kinase/akt, and stat proteins. SIGNOR-127540 SIGNOR-MonoMAC Monocyte: Macrophage differentiation CSF1R protein P07333 UNIPROT CSF1R protein P07333 UNIPROT up-regulates phosphorylation Tyr723 SSQGVDTyVEMRPVS 9606 BTO:0001271 15297464 YES lperfetto Csf-1r homodimerizes and autophosphorylates on six tyrosines in the cytoplasmic portion of the receptor. Tyr807 is located in the activation loop of the kinase domain (9) and its phosphorylation is important for kinase activity (10). The remaining tyrosines serve as binding sites for proteins containing src homology 2 (sh2) binding domains. Three sites are found in the ki: grb2/mona (tyr697) (11, 12), p85 subunit of phosphatidylinositol 3-kinase (tyr721) (13), and stat1 (tyr706) (14), the c-cbl binding site is in the cooh terminus (tyr974) (15, 16), and the src family kinase (sfk) binding site is in the jmd (y559) (17). These molecules further propagate the csf-1 signal through activation of ras/erk, phosphatidylinositol 3-kinase/akt, and stat proteins. SIGNOR-127614 SIGNOR-MonoMAC Monocyte: Macrophage differentiation CSF1R protein P07333 UNIPROT CSF1R protein P07333 UNIPROT up-regulates phosphorylation Tyr809 DIMNDSNyIVKGNAR 9606 BTO:0001271 15297464 YES lperfetto Csf-1r homodimerizes and autophosphorylates on six tyrosines in the cytoplasmic portion of the receptor. Tyr807 is located in the activation loop of the kinase domain (9) and its phosphorylation is important for kinase activity (10). The remaining tyrosines serve as binding sites for proteins containing src homology 2 (sh2) binding domains. Three sites are found in the ki: grb2/mona (tyr697) (11, 12), p85 subunit of phosphatidylinositol 3-kinase (tyr721) (13), and stat1 (tyr706) (14), the c-cbl binding site is in the cooh terminus (tyr974) (15, 16), and the src family kinase (sfk) binding site is in the jmd (y559) (17). These molecules further propagate the csf-1 signal through activation of ras/erk, phosphatidylinositol 3-kinase/akt, and stat proteins. SIGNOR-127618 SIGNOR-MonoMAC Monocyte: Macrophage differentiation CSF1R protein P07333 UNIPROT SOCS1 protein O15524 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24890514 NO miannu CSF-1R also induces the expression/activation of several other regulators of multipotent progenitor proliferation/differentiation (Fig. 4A). These include [‚Ķ] the adaptor proteins suppressor of cytokine signaling 1 (Socs1) SIGNOR-255574 SIGNOR-MonoMAC Monocyte: Macrophage differentiation CSF1R protein P07333 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 24890514 NO apalma The Erk1/2 pathway has a central role in CSF-1R-regulated myeloid differentiation. CSF-1 induces early (peaking at ‚àº5 min) and persistent (starting at 1 h) waves of MEK/Erk1/2 phosphorylation SIGNOR-255572 SIGNOR-MonoMAC Monocyte: Macrophage differentiation CSF2RA protein P15509 UNIPROT CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR form complex binding 9606 9680354 YES apalma The high-affinity GMR is known to be composed of a specific ligand-binding alpha subunit (GMRα) and a common beta subunit (βc), which is also a component of the interleukins-3 (IL-3) and -5 (IL-5) receptors. SIGNOR-255582 SIGNOR-MonoMAC Monocyte: Macrophage differentiation PLCG2 protein P16885 UNIPROT Macrophage_differentiation phenotype SIGNOR-PH99 SIGNOR up-regulates 9606 24890514 NO apalma Studies with multipotent precursor cell lines (Fig. 4A) indicate that CSF-1R Tyr-807 and Tyr-721 promote macrophage differentiation via the PLC-Œ≥2 pathway SIGNOR-255571 SIGNOR-MonoMAC Monocyte: Macrophage differentiation IL34 protein Q6ZMJ4 UNIPROT CSF1R protein P07333 UNIPROT up-regulates activity binding 9606 BTO:0000876 BTO:0001103 24890514 YES apalma The CSF-1 receptor (CSF-1R) is activated by the homodimeric growth factors colony-stimulating factor-1 (CSF-1) and interleukin-34 (IL-34) SIGNOR-255569 SIGNOR-MonoMAC Monocyte: Macrophage differentiation CSF2RB protein P32927 UNIPROT CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR form complex binding 9606 BTO:0000876 BTO:0001103 9680354 YES apalma The high-affinity GMR is known to be composed of a specific ligand-binding alpha subunit (GMRα) and a common beta subunit (βc), which is also a component of the interleukins-3 (IL-3) and -5 (IL-5) receptors. SIGNOR-255583 SIGNOR-MT Macrophage: TGF beta SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 27418133 NO The SMAD2/3 and PI3K/AKT signaling pathways were crucial for TGF-?-induced SNAIL overexpression in THP-1 cells. These findings suggest that TGF-? skews macrophage polarization towards a M2-like phenotype via SNAIL up-regulation, and blockade of TGF-?/SNAIL signaling restores the production of pro-inflammatory cytokines SIGNOR-253588 SIGNOR-MT Macrophage: TGF beta SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 27418133 NO The SMAD2/3 and PI3K/AKT signaling pathways were crucial for TGF-?-induced SNAIL overexpression in THP-1 cells. These findings suggest that TGF-? skews macrophage polarization towards a M2-like phenotype via SNAIL up-regulation, and blockade of TGF-?/SNAIL signaling restores the production of pro-inflammatory cytokines SIGNOR-253587 SIGNOR-MT Macrophage: TGF beta TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity binding 9606 22703233 YES lperfetto TGFbeta signals are transmitted via a cell surface receptor complex consisting of the TGFbeta type I receptor (TbetaRI) and TGFbeta type II receptor (TbetaRII). To initiate signal transduction, TGFbeta binds to TbetaRII, which in turn recruits TbetaRI, leading to the formation of a tetrameric receptor complex. SIGNOR-249548 SIGNOR-MT Macrophage: TGF beta SMAD2 protein Q15796 UNIPROT SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR form complex binding 9606 phosphorylation:Ser465;Ser467 SPSVRCSsMS;SVRCSSMs 11274206 YES gcesareni the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4 SIGNOR-235188 SIGNOR-MT Macrophage: TGF beta SMAD4 protein Q13485 UNIPROT SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR form complex binding 9606 11274206 YES gcesareni the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4 SIGNOR-235178 SIGNOR-MT Macrophage: TGF beta SMAD3 protein P84022 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR form complex binding 9606 9843571 YES lperfetto TGF-beta treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. SIGNOR-229557 SIGNOR-MT Macrophage: TGF beta ZFYVE9 protein O95405 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity relocalization 9606 9865696 YES lperfetto We now identify SARA (for Smad anchor for receptor activation), a FYVE domain protein that interacts directly with Smad2 and Smad3. SARA functions to recruit Smad2 to the TGFbeta receptor by controlling the subcellular localization of Smad2 and by interacting with the TGFbeta receptor complex. SIGNOR-232126 SIGNOR-MT Macrophage: TGF beta ZFYVE9 protein O95405 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity relocalization 9606 20515759 YES lperfetto Smad anchor for receptor activation (SARA) is known as Smad cofactor that interacts directly with Smad2/3 and functions to recruit Smad2/3 to the TGF-beta receptor. SIGNOR-165786 SIGNOR-MT Macrophage: TGF beta TGFBR1 protein P36897 UNIPROT ZFYVE9 protein O95405 UNIPROT up-regulates activity binding 9606 9865696 YES lperfetto Sara functions to recruit smad2 to the tgfbeta receptor by controlling the subcellular localization of smad2 and by interacting with the tgfbeta receptor complex SIGNOR-62868 SIGNOR-MT Macrophage: TGF beta TGFBR1 protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser425 SIRCSSVs 10090 BTO:0005493;BTO:0000165 19458083 YES lperfetto A major event leading to Smad3 activation is the TGF-beta-induced, TbetaRI-mediated phosphorylation at two C-terminal serine residues, Ser-423 and Ser-425, which triggers dissociation of Smad3 from its receptors to form a complex with Smad4 and accumulate in the nucleus SIGNOR-235380 SIGNOR-MT Macrophage: TGF beta TGFBR1 protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser423 SPSIRCSsVS 10090 BTO:0005493;BTO:0000165 19458083 YES lperfetto A major event leading to smad3 activation is the tgf-beta-induced, tbetari-mediated phosphorylation at two c-terminal serine residues, ser-423 and ser-425, which triggers dissociation of smad3 from its receptors to form a complex with smad4 and accumulate in the nucleus SIGNOR-235385 SIGNOR-MT Macrophage: TGF beta TGFBR1 protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation Ser467 SVRCSSMs 9534 9346908 YES lperfetto Recently, it was demonstrated that Smad2 interacts transiently with and is a direct substrate of the transforming growth factor-beta (TGF-beta) type I receptor, TbetaRI. Phosphorylation sites on Smad2 were localized to a carboxyl-terminal fragment containing three serine residues at positions 464, 465, and 467. These results indicate that receptor-dependent phosphorylation of Smad2 on serines 465 and 467 is required in mammalian cells to permit association with Smad4 and to propagate TGF-_ signals. SIGNOR-235995 SIGNOR-MyoATR Myofiber: Glucocorticoid-induced atrophy dexamethasone chemical CHEBI:41879 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 20956975 YES fspada Glucocorticoids, such as dexamethasone, have been used as in vitro inducers of adipogenesis. However, the roles of the glucocorticoid receptor (gr) in adipogenesis have not been well characterized yet. Here, we show that inhibition of gr activity using the gr antagonist ru486 prevents human mesenchymal stem cell and mouse embryonic fibroblast (mef) differentiation into adipocytes SIGNOR-168562 SIGNOR-MyoATR Myofiber: Glucocorticoid-induced atrophy FOXO3 protein O43524 UNIPROT TRIM63 protein Q969Q1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 21798082 NO lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. SIGNOR-236551 SIGNOR-MyoATR Myofiber: Glucocorticoid-induced atrophy FOXO3 protein O43524 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 21798082 NO lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. SIGNOR-235715 SIGNOR-MyoATR Myofiber: Glucocorticoid-induced atrophy FOXO3 protein O43524 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15109499 NO lperfetto Moreover, constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers. SIGNOR-232174 SIGNOR-MyoATR Myofiber: Glucocorticoid-induced atrophy FBXO32 protein Q969P5 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 25096180 NO Muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx)/atrogin-1 were identified more than 10 years ago as two muscle-specific E3 ubiquitin ligases that are increased transcriptionally in skeletal muscle under atrophy-inducing conditions, making them excellent markers of muscle atrophy SIGNOR-252072 SIGNOR-MyoATR Myofiber: Glucocorticoid-induced atrophy FBXO32 protein Q969P5 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 BTO:0001103 20871233 NO Atrogin-1, but not MuRF-1, was induced at both the gene and protein level as ApcMin/+ mice aged from 3 to 6 months of age, going from a pre-cachectic to a cachectic state. Atrogin-1 mRNA and protein levels were also elevated in ApcMin/+ mice when we over-expressed IL-6 in the circulation. SIGNOR-255343 SIGNOR-MyoATR Myofiber: Glucocorticoid-induced atrophy FBXO32 protein Q969P5 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 BTO:0001103 11717410 NO Atrogin-1 is one of the few examples of an F-box protein or Ub-protein ligase (E3) expressed in a tissue-specific manner and appears to be a critical component in the enhanced proteolysis leading to muscle atrophy in diverse diseases SIGNOR-255344 SIGNOR-MyoATR Myofiber: Glucocorticoid-induced atrophy TRIM63 protein Q969Q1 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates activity 10090 25549588 NO areggio Muscle-specific ubiq- uitin ligases, muscle-specific RING-finger 1 (MURF1; also known as TRIM63)12 and atrogin 1 (also known as MAFBX), are markedly induced in almost all types of atrophy. SIGNOR-254993 SIGNOR-MyoATR Myofiber: Glucocorticoid-induced atrophy NR3C1 protein P04150 UNIPROT TRIM63 protein Q969Q1 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18612045 NO areggio Consistent with these findings, DEX-induced upregulation of MuRF1 is significantly attenuated in mice expressing a homodimerization-deficient GR despite no effect on the degree of muscle loss in these mice vs. their wild-type counterparts. Finally, chromatin immunoprecipitation analysis reveals that both GR and FOXO1 bind to the endogenous MuRF1 promoter in C(2)C(12) myotubes, and IGF-I inhibition of DEX-induced MuRF1 expression correlates with the loss of FOXO1 binding. SIGNOR-254992 SIGNOR-MyoATR Myofiber: Glucocorticoid-induced atrophy NR3C1 protein P04150 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates quantity transcriptional regulation 10090 22848740 YES miannu We show that FOXO3 is an immediate early glucocorticoid receptor (GR) target, whose transcription is even further enhanced by conditions that mimic metabolic stress. SIGNOR-255759 SIGNOR-MyocCA Myoblast: Calcium-mediated fusion Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation 9606 21880741 YES miannu Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. SIGNOR-255463 SIGNOR-MyocCA Myoblast: Calcium-mediated fusion calcium(2+) smallmolecule CHEBI:29108 ChEBI Calcineurin complex SIGNOR-C155 SIGNOR up-regulates activity chemical activation 9606 21880741 YES miannu Except for nfat5, nfatc1c4 are activated upon a rise in intracellular ca2+, which stimulates the serine/threonine phosphatase activity of calcineurin the ca2+-calcineurin signal is the most important signal for regulating nfat activation, but the signal that leads to ca2+ influx during neural tube differentiation is still unclear. SIGNOR-255462 SIGNOR-MyocCA Myoblast: Calcium-mediated fusion NFATC2 protein Q13469 UNIPROT MYOF protein Q9NZM1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 23612709 NO miannu Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin SIGNOR-255465 SIGNOR-MyocCA Myoblast: Calcium-mediated fusion NFATC2 protein Q13469 UNIPROT IL4 protein P05112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 11956291 NO IRF4 synergizes with NFATc2 and the IL-4-inducing transcription factor, c-maf, to augment IL-4 promoter activity as well as to elicit significant levels of endogenous IL-4 production SIGNOR-254502 SIGNOR-MyocCA Myoblast: Calcium-mediated fusion NFATC2 protein Q13469 UNIPROT IL4 protein P05112 UNIPROT up-regulates transcriptional regulation 9606 23612709 NO Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin SIGNOR-255460 SIGNOR-MyocCA Myoblast: Calcium-mediated fusion IL4 protein P05112 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 10090 12757709 NO miannu These data demonstrate that following myotube formation, myotubes recruit myoblast fusion by secretion of IL-4, leading to muscle growth SIGNOR-255896 SIGNOR-MyocCA Myoblast: Calcium-mediated fusion MYOF protein Q9NZM1 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 9606 23612709 NO Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin SIGNOR-255466 SIGNOR-MyocGH Myoblast: GH-mediated fusion NPNT protein Q6UXI9 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 9606 23612709 NO miannu The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion SIGNOR-255458 SIGNOR-MyocGH Myoblast: GH-mediated fusion NFATC2 protein Q13469 UNIPROT MYOF protein Q9NZM1 UNIPROT up-regulates transcriptional regulation 9606 23612709 NO Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin SIGNOR-255461 SIGNOR-MyocGH Myoblast: GH-mediated fusion NFATC2 protein Q13469 UNIPROT IL4 protein P05112 UNIPROT up-regulates transcriptional regulation 9606 23612709 NO Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin SIGNOR-255460 SIGNOR-MyocGH Myoblast: GH-mediated fusion GH1 protein P01241 UNIPROT GHR protein P10912 UNIPROT up-regulates activity binding 9606 7862673 YES miannu Although growth hormone (GH) receptors (GHRs) in many species bind human (h) GH as well as their own GH, the hGHR only binds primate GH. SIGNOR-255451 SIGNOR-MyocGH Myoblast: GH-mediated fusion KLF4 protein O43474 UNIPROT NPNT protein Q6UXI9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0005787 BTO:0001103 23612709 NO miannu The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion SIGNOR-255457 SIGNOR-MyocGH Myoblast: GH-mediated fusion KLF2 protein Q9Y5W3 UNIPROT NPNT protein Q6UXI9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0005787 BTO:0001103 23612709 NO miannu The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion SIGNOR-255456 SIGNOR-MyocGH Myoblast: GH-mediated fusion GHR protein P10912 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates activity phosphorylation 9606 BTO:0005787 BTO:0001103 23612709 YES miannu The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion SIGNOR-255452 SIGNOR-MyocGH Myoblast: GH-mediated fusion GHR protein P10912 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates 9606 23612709 NO miannu Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin. Possible stimuli for NFATc2 activation are PGF2α and GH. SIGNOR-255459 SIGNOR-MyocGH Myoblast: GH-mediated fusion MAPK7 protein Q13164 UNIPROT KLF2 protein Q9Y5W3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0005787 BTO:0001103 23612709 NO miannu The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion SIGNOR-255454 SIGNOR-MyocGH Myoblast: GH-mediated fusion MAPK7 protein Q13164 UNIPROT KLF4 protein O43474 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23612709 NO miannu The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion SIGNOR-255455 SIGNOR-MyocGH Myoblast: GH-mediated fusion IL4 protein P05112 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 10090 12757709 NO miannu These data demonstrate that following myotube formation, myotubes recruit myoblast fusion by secretion of IL-4, leading to muscle growth SIGNOR-255896 SIGNOR-MyocGH Myoblast: GH-mediated fusion MAP2K5 protein Q13163 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates activity phosphorylation 9606 BTO:0005787 BTO:0001103 23612709 YES miannu The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion SIGNOR-255453 SIGNOR-MyocGH Myoblast: GH-mediated fusion MYOF protein Q9NZM1 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 9606 23612709 NO Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin SIGNOR-255466 SIGNOR-MyocIL6HYPER Myoblast: IL6 and hypertrophy MYC protein P01106 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12835716 YES gcesareni C-myc directly activates transcription of cyclin d1, cyclin d2 and cdk4, and leads to cdk 4/6 activation SIGNOR-102731 SIGNOR-MyocIL6HYPER Myoblast: IL6 and hypertrophy MYC protein P01106 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 21408055 NO andrea cerquone perpetuini We have demonstrated that following muscle damage, phosphorylated STAT3 (p-STAT3) in SCs increases early (within one hour), inducing downstream target genes (i.e. GP130 and SOCS3), which further regulate the increase in STAT3 production and response (as induced via IL-6), leading to increased cMyc expression, which drives cell proliferation SIGNOR-255414 SIGNOR-MyocIL6HYPER Myoblast: IL6 and hypertrophy MYC protein P01106 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 NO gcesareni C-myc has emerged as one of the central regulators of mammalian cell proliferation. SIGNOR-56572 SIGNOR-MyocIL6HYPER Myoblast: IL6 and hypertrophy JAK2 protein O60674 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000599 9575217 YES lperfetto Activation of wild type stat3: il-6 treatment causes stat3 recruitment to receptor tyrosine phosphopeptides (gp130) where it is phosphorylated on tyrosine 705 (y) by jak kinase SIGNOR-236463 SIGNOR-MyocIL6HYPER Myoblast: IL6 and hypertrophy JAK2 protein O60674 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000599 9575217 YES lperfetto Inactive cytoplasmic STATs are recruited to the activated receptor by docking of the STAT SH2 domain to selected receptor tyrosine phosphopeptides, where they are in turn phosphorylated on a single tyrosine by Jak kinases. Has been identified tyrosine 705 of Stat3 as the likely site of phosphorylation by Jak kinases during signal transduction. SIGNOR-238638 SIGNOR-MyocIL6HYPER Myoblast: IL6 and hypertrophy IL6 protein P05231 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity -1 8511589 NO lperfetto The biological functions of interleukin-6 (IL-6) are mediated through a signal-transducing component of the IL-6 receptor, gp130, which is associated with the ligand-occupied IL-6 receptor (IL-6R) protein. Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130. Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein. Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130. SIGNOR-238617 SIGNOR-MyocIL6HYPER Myoblast: IL6 and hypertrophy IL6 protein P05231 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity binding 9606 BTO:0001271 15895091 YES miannu A crystal structure of the ligand-binding domains of gp130 in complex with human interleukin-6 (il-6) and its a-receptor (il-6ralpha) revealed a hexameric architecture in which the gp130 membrane-distal regions were approximately 100 a apart, in contrast to the close apposition seen between short cytokine receptor complexes. SIGNOR-48041 SIGNOR-MyocIL6HYPER Myoblast: IL6 and hypertrophy IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates activity binding 9606 18923185 YES miannu IL-6 and IL-11 are the only members of the family that signal via the induction of a gp130 homodimer after binding their specific -receptors, IL-6R and IL-11R. When IL-6 binds to the homodimerized IL-6Rα/gp130Rβ, it results in a signaling cascade that is initiated by the autophoshorylation and activation of JAK. SIGNOR-255324 SIGNOR-MyocIL6HYPER Myoblast: IL6 and hypertrophy IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 23663276 YES milica In classical il-6 signaling, the cytokine first binds to the membrane-bound il-6 receptor (il-6r;cd126) that is induced to associate with a homodimer of gp130 which then transmits the intracellular signal. SIGNOR-202030 SIGNOR-MyocIL6HYPER Myoblast: IL6 and hypertrophy IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 15895091 YES gcesareni We show that the augmentation of the il6 signal by recombinant il6 receptors (ril6r) delivery allows the functional recovery of phagocytes in a peritonitis mouse model. SIGNOR-137236 SIGNOR-MyocIL6HYPER Myoblast: IL6 and hypertrophy IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 8676083 YES fspada We first observed that cultured mouse embryonic dorsal root ganglia exhibited dramatic neurite extension by simultaneous addition of il-6 and soluble il-6r (sil-6r), a complex that is known to interact with and activate a signal transducing receptor component, gp130 SIGNOR-42866 SIGNOR-MyocIL6HYPER Myoblast: IL6 and hypertrophy STAT3 protein P40763 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 25194572 NO miannu Here we show that IL-6-activated Stat3 signaling regulates satellite cell behavior, promoting myogenic lineage progression through myogenic differentiation 1 (Myod1) regulation. IL-6 stimulation promoted an increase in the mRNA levels of both Stat3 and Myod1. Stat3 mediated this effect, as IL-6‚Äìdependent Myod1 upregulation was impaired after infection with the shStat3 lentivirus. SIGNOR-255416 SIGNOR-MyocIL6HYPER Myoblast: IL6 and hypertrophy STAT3 protein P40763 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression 9606 BTO:0001103 21408055 NO andrea cerquone perpetuini Additionally, cMyc, a STAT3 downstream gene, was significantly up-regulated in SCs at T24 versus PRE [...]An increase in the number of cMyc+ SCs indicated that human SCs were induced to proliferate under the control of STAT3 signaling. SIGNOR-255413 SIGNOR-MyocIL6HYPER Myoblast: IL6 and hypertrophy STAT3 protein P40763 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 18177723 NO andrea cerquone perpetuini We identified cyclin D1 as a STAT3 target gene product downregulated in satellite cells from IL-6-deficient muscle in vitro and in vivo. SIGNOR-255411 SIGNOR-MyocIL6HYPER Myoblast: IL6 and hypertrophy STAT3 protein P40763 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16510571 NO lperfetto Mutagenesis of STAT3 binding sites within the cyclin D1 promoter and chromatin immunoprecipitation studies showed an association between STAT3 and the transcriptional regulation of the human cyclin D1 gene. SIGNOR-253049 SIGNOR-MyocIL6HYPER Myoblast: IL6 and hypertrophy STAT3 protein P40763 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0002314 25194572 NO lperfetto STAT3 signaling controls satellite cell expansion and skeletal muscle repair SIGNOR-245048 SIGNOR-MyocIL6HYPER Myoblast: IL6 and hypertrophy MYOD1 protein P15172 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0001103 16275751 NO andrea cerquone perpetuini Together, these results support the notion that Myf5 functions toward myoblast proliferation, whereas MyoD prepares myoblasts for efficient differentiation. SIGNOR-255417 SIGNOR-MyocIL6HYPER Myoblast: IL6 and hypertrophy IL6R protein P08887 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 23663276 YES milica In classical il-6 signaling, the cytokine first binds to the membrane-bound il-6 receptor (il-6r;cd126) that is induced to associate with a homodimer of gp130 which then transmits the intracellular signal. SIGNOR-202033 SIGNOR-MyocIL6HYPER Myoblast: IL6 and hypertrophy IL6R protein P08887 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 BTO:0000785 11238858 YES gcesareni Part of the receptor for interleukin 6. Binds to il6 with low affinity, but does not transduce a signal. Signal activation necessitate an association with il6st. Activation may lead to the regulation of the immune response, acute-phase reactions and hematopoiesis. SIGNOR-105504 SIGNOR-MyocIL6HYPER Myoblast: IL6 and hypertrophy IL6R protein P08887 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation 9606 23869758 YES miannu On binding of IL-6 to its receptor IL-6R, JAK2 is phosphorylated, then STAT3 is phosphorylated by JAK2 SIGNOR-254405 SIGNOR-MyocIL6HYPER Myoblast: IL6 and hypertrophy IL6ST protein P40189 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity phosphorylation Ser661 NVPDPSKsHIAQWSP -1 8511589 YES lperfetto The biological functions of interleukin-6 (IL-6) are mediated through a signal-transducing component of the IL-6 receptor, gp130, which is associated with the ligand-occupied IL-6 receptor (IL-6R) protein. Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130. Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein. Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130. SIGNOR-238625 SIGNOR-MyocIL6HYPER Myoblast: IL6 and hypertrophy IL6ST protein P40189 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity phosphorylation Ser659 WPNVPDPsKSHIAQW -1 8511589 YES lperfetto The biological functions of interleukin-6 (IL-6) are mediated through a signal-transducing component of the IL-6 receptor, gp130, which is associated with the ligand-occupied IL-6 receptor (IL-6R) protein. Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130. Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein. Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130. SIGNOR-238621 SIGNOR-MyocIL6HYPER Myoblast: IL6 and hypertrophy IL6ST protein P40189 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 9716487 YES lperfetto All IL-6-type cytokines recruit gp130to their receptot complexes They either signal via gp130 alone [8] or in combination with LIFR [9] or the recently cloned OSMR [10], which are all able to activate Jaks proteins. Two tyrosine residues at the corresponding positions of Jak2 (tyrosine-1007 and tyrosine-1008) were found to be phosphorylated, and a single mutation of tyrosine-1007 eliminated essentially all tyrosine kinase activity [59]. SIGNOR-238630 SIGNOR-MyocIL6HYPER Myoblast: IL6 and hypertrophy IL6ST protein P40189 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1008 LPQDKEYyKVKEPGE 9606 9716487 YES lperfetto All IL-6-type cytokines recruit gp130to their receptot complexes They either signal via gp130 alone [8] or in combination with LIFR [9] or the recently cloned OSMR [10], which are all able to activate Jaks proteins. Two tyrosine residues at the corresponding positions of Jak2 (tyrosine-1007 and tyrosine-1008) were found to be phosphorylated, and a single mutation of tyrosine-1007 eliminated essentially all tyrosine kinase activity [59]. SIGNOR-238634 SIGNOR-MyoIGF1R Myofiber: IGF1R RPS6K proteinfamily SIGNOR-PF26 SIGNOR IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 BTO:0001103 21798082 YES lperfetto Negative feedback involves s6k, which inactivates irs by phosphorylation at multiple sites, thus inducing its degradation and altered cell localization. SIGNOR-252787 SIGNOR-MyoIGF1R Myofiber: IGF1R mTORC1 complex SIGNOR-C3 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr390 DSKFTRQtPVDSPDD 9606 11914378 YES azuccotti Thr229 phosphorylation requires prior phosphorylation of the Ser/Thr-Pro sites in the autoinhibitory domain and Thr389 in the linker domain [..]. Moreover, in vitro mTOR directly phosphorylates Ser371, and this event modulates Thr389phosphorylation by mTOR, compatible with earlier in vivo findings. SIGNOR-255842 SIGNOR-MyoIGF1R Myofiber: IGF1R mTORC1 complex SIGNOR-C3 SIGNOR Cell_growth phenotype SIGNOR-PH33 SIGNOR up-regulates 9606 23863160 NO lperfetto Cellular energy and nutrient status will dictate whether mTORC1 takes over and drives cell growth or conversely whether AMPK becomes active once again to drive consecutive waves of autophagy thorough ULK1. SIGNOR-209919 SIGNOR-MyoIGF1R Myofiber: IGF1R mTORC2 complex SIGNOR-C2 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000132 21592956 YES lperfetto Protein kinase B (PKB, Akt) is a Ser/Thr kinase involved in the regulation of cell survival, proliferation, and metabolism and is activated by dual phosphorylation on Thr(308) in the activation loop and Ser(473) in the hydrophobic motif. It plays a contributory role to platelet function, although little is known about its regulation. In this study, we investigated the role of the mammalian target of rapamycin complex (mTORC)-2 in Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1. SIGNOR-217012 SIGNOR-MyoIGF1R Myofiber: IGF1R PI3K complex SIGNOR-C156 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity 9606 BTO:0000150 19573809 NO lperfetto However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth SIGNOR-252704 SIGNOR-MyoIGF1R Myofiber: IGF1R PI3K complex SIGNOR-C156 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001103 15829723 YES apalma IGF-I binding to its receptor activates the kinase activity of the receptor, which then recruits the insulin response substrate-1, causing activation of phosphatidyl-inositol-3 kinase (PI3K) to phosphorylate Akt. SIGNOR-255106 SIGNOR-MyoIGF1R Myofiber: IGF1R IRS1 protein P35568 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 10116 BTO:0001103 21798082 YES lperfetto Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate (pip2). SIGNOR-252694 SIGNOR-MyoIGF1R Myofiber: IGF1R IRS1 protein P35568 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 20966354 YES lperfetto Irs proteins are capable of both regulating and activating pi3k, depending on the cell of origin. SIGNOR-252695 SIGNOR-MyoIGF1R Myofiber: IGF1R FOXO1 protein Q12778 UNIPROT TRIM63 protein Q969Q1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21798082 NO lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. SIGNOR-235712 SIGNOR-MyoIGF1R Myofiber: IGF1R FOXO1 protein Q12778 UNIPROT TRIM63 protein Q969Q1 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18612045 NO lperfetto Transcriptional reporter assays performed in both HepG2 and C2C12 cells demonstrate that the MuRF1 promoter is highly responsive to dexamethasone-activated glucocorticoid receptor (GR) and FoxO1 individually, while co-overexpression of GR and FoxO1 leads to a dramatic synergistic increase in reporter activity SIGNOR-235367 SIGNOR-MyoIGF1R Myofiber: IGF1R AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 YES lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-236159 SIGNOR-MyoIGF1R Myofiber: IGF1R AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 YES lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-236163 SIGNOR-MyoIGF1R Myofiber: IGF1R AKT1 protein P31749 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 BTO:0001103 15829723 YES apalma Once phosphorylated, Akt can act on a broad spectrum of substrates that can influence cell survival and proliferation and protein synthesis (65). Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K SIGNOR-255844 SIGNOR-MyoIGF1R Myofiber: IGF1R IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr1179 GLENGLNyIDLDLVK 9606 17827393 YES gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). SIGNOR-157730 SIGNOR-MyoIGF1R Myofiber: IGF1R IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr1229 SSEDLSAyASISFQK 9606 17827393 YES gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). SIGNOR-157734 SIGNOR-MyoIGF1R Myofiber: IGF1R IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr465 GEEELSNyICMGGKG 9606 17827393 YES gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). SIGNOR-157738 SIGNOR-MyoIGF1R Myofiber: IGF1R IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr612 TLHTDDGyMPMSPGV 9606 17827393 YES gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). SIGNOR-157742 SIGNOR-MyoIGF1R Myofiber: IGF1R IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr632 GRKGSGDyMPMSPKS 9606 17827393 YES gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). SIGNOR-157746 SIGNOR-MyoIGF1R Myofiber: IGF1R IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr896 EPKSPGEyVNIEFGS 9606 17827393 YES gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). SIGNOR-157750 SIGNOR-MyoIGF1R Myofiber: IGF1R IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr941 EETGTEEyMKMDLGP 9606 17827393 YES gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). SIGNOR-157754 SIGNOR-MyoIGF1R Myofiber: IGF1R IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr989 VPSSRGDyMTMQMSC 9606 17827393 YES gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). SIGNOR-157758 SIGNOR-MyoIGF1R Myofiber: IGF1R IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation 9606 BTO:0001103 15829723 YES apalma IGF-I binding to its receptor activates the kinase activity of the receptor, which then recruits the insulin response substrate-1, causing activation of phosphatidyl-inositol-3 kinase (PI3K) to phosphorylate Akt. SIGNOR-255104 SIGNOR-MyoIGF1R Myofiber: IGF1R IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation 9606 21798082 YES gcesareni Binding of IGF1 to its receptor leads to activation of its intrinsic tyrosine kinase and autophosphorylation, thus generating docking sites for insulin receptor substrate (IRS), which is also phosphorylated by the IGF1 receptor. SIGNOR-175665 SIGNOR-MyoIGF1R Myofiber: IGF1R IGF1 protein P05019 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity binding 9606 21798082 YES lperfetto Binding of IGF1 to its receptor leads to activation of its intrinsic tyrosine kinase and autophosphorylation, thus generating docking sites for insulin receptor substrate (IRS), which is also phosphorylated by the IGF1 receptor. SIGNOR-175662 SIGNOR-MyoIGF1R Myofiber: IGF1R IGF1 protein P05019 UNIPROT IGF1R protein P08069 UNIPROT up-regulates binding 9606 19029956 YES lperfetto At the cellular level, the ligands IGF1, IGF2 and insulin bind to various members of the insulin receptor (IR) - IGF1 receptor (IGF1R) family. SIGNOR-182484 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation 9606 17900900 YES lperfetto We have recently found that AMPK phosphorylates human FOXO3 in mammalian cells at novel regulatory sites that are distinct from the AKT sites SIGNOR-216481 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser399 DNITLPPsQPSPTGG 9606 BTO:0000007 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-249668 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser413 GLMQRSSsFPYTTKG 9606 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-249678 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser555 RALSNSVsNMGLSES 9606 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-249682 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser626 SLECDMEsIIRSELM 9606 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-249688 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Thr179 SSPDKRLtLSQIYEW 9606 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-238813 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser588 QTLSDSLsGSSLYST 9606 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-249685 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy AMPK complex SIGNOR-C15 SIGNOR FOXO1 protein Q12778 UNIPROT up-regulates phosphorylation 9606 18394876 YES lperfetto The energy sensor AMP-activated protein kinase (AMPK) has been shown to directly phosphorylate FoxO factors at six regulatory sites that are distinct from the Akt phosphorylation sites, resulting in FoxO activation. SIGNOR-216478 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy AMPK complex SIGNOR-C15 SIGNOR AMPK complex SIGNOR-C15 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 17728241 YES lperfetto Mutation of serine 108 to alanine, an autophosphorylation site within the glycogen binding domain of the beta1 subunit, almost completely abolishes activation of ampk by a-769662 in cells and in vitro, while only partially reducing activation by ampk SIGNOR-216411 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy AMPK complex SIGNOR-C15 SIGNOR AMPK complex SIGNOR-C15 SIGNOR unknown phosphorylation 9606 BTO:0000007 11171104 YES lperfetto In contrast, the phosphorylation site mutations, ss24, 25aa and s182a, while having no effects on enzyme activity, are associated with nuclear redistribution of the subunit. SIGNOR-216415 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy AMPK complex SIGNOR-C15 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity phosphorylation 9606 23863160 YES lperfetto AMPK inhibits mTORC1 through two means: first, through phosphorylation of TSC2 to activate its GAP (GTPase-activating protein) activity that converts Rheb into an inactive GDP-bound state, thus switching off mitogenic stimulation of mTORC1 [31], and, secondly, through phosphorylation of raptor at Ser722 and Ser792, which leads to 14-3-3 protein binding and mTORC1 inhibition SIGNOR-209862 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy AMPK complex SIGNOR-C15 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity phosphorylation 9606 20083114 YES lperfetto A recent study revealed that ampk can inhibit mtorc1 independently of tsc2 by phosphorylating raptor at ser863. SIGNOR-216422 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy AMPK complex SIGNOR-C15 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity phosphorylation 9606 BTO:0000007 18439900 YES lperfetto The phosphorylation of raptor by ampk is required for the inhibition of mtorc1 and cell-cycle arrest induced by energy stress. SIGNOR-216430 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy AMPK complex SIGNOR-C15 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity phosphorylation 10090 BTO:0002572 21460634 YES miannu AMP-activated protein kinase (AMPK), which is activated by LKB1/Strad/Mo25 upon high AMP levels, stimulates autophagy by inhibiting mTORC1. SIGNOR-216418 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-183620 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-183612 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-183616 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249645 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249646 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249647 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 21440011 YES lperfetto Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs SIGNOR-252348 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser319 TFRPRTSsNASTISG 9606 11237865 YES lperfetto The transcription factor, forkhead in rhabdomyosarcoma (fkhr), is phosphorylated at three amino acid residues (thr-24, ser-256 and ser-319) by protein kinase b (pkb)alpha.Fkhr (forkhead in rhabdomyosarcoma), afx (all1 fused gene from chromosome x) and fkhrl1 (fkhr-like 1) are phosphorylated directly by pkb in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus SIGNOR-252349 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 21798082 YES lperfetto Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b). SIGNOR-252352 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 YES lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. These results indicate that phosphorylation by PKB/Akt negatively regulates FKHR1 by promoting export from the nucleus. SIGNOR-252346 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 YES lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-252347 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 10090 BTO:0002572 18423396 YES lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation SIGNOR-252350 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates relocalization 10090 BTO:0002572 18423396 YES lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation SIGNOR-252351 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 10090 BTO:0000011 19593385 YES lperfetto In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis SIGNOR-252817 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy SOCS3 protein O14543 UNIPROT IL6ST protein P40189 UNIPROT down-regulates activity binding 9606 23454976 YES miannu SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition. The inhibitory protein SOCS3 plays a key part in the immune and hematopoietic systems by regulating signaling induced by specific cytokines. SOCS3 functions by inhibiting the catalytic activity of Janus kinases (JAKs) that initiate signaling within the cell. SIGNOR-255328 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy SOCS3 protein O14543 UNIPROT IL6ST protein P40189 UNIPROT down-regulates activity binding 9606 BTO:0000887;BTO:0001103 19620279 YES miannu We now show that SOCS1, SOCS3, and PIAS1 promote myogenic differentiation by specifically inhibiting the LIF-induced JAK1/STAT1/STAT3 pathway via distinct targets; whereas SOCS1 and SOCS3 selectively bind and inhibit JAK1 and gp130, respectively, PIAS1 targets mainly the activated STAT1 and prevents its binding to DNA. SIGNOR-202045 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy SOCS3 protein O14543 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity 9606 24600449 NO miannu A main role of SOCS3 results from its binding to both the JAK kinase and the cytokine receptor, which results in the inhibition of STAT3 activation. SIGNOR-255330 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy SOCS3 protein O14543 UNIPROT STAT3 protein P40763 UNIPROT down-regulates 9606 BTO:0000801 21628332 NO lperfetto SOCS3 attenuates IL-6-induced STAT3 anti-inflammatory effects, as well as IL-4-induced insulin receptor substrate-2/PI3K-mediated gene expression. SIGNOR-249567 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy SOCS3 protein O14543 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity binding 9606 24600449 YES miannu The ability of SOCS3 to simultaneously bind to JAK and to the cytokine receptor explains the specificity of the suppression. SOCS3 binds JAK and gp130 receptor simultaneously, using two opposing surfaces: while the phosphotyrosine-binding groove on the SOCS3 SH2 domain is occupied by the gp130 receptor, a subdomain in the SH2 domain of SOCS3 is also required for inhibition of JAK, binding in a phospho-independent manner to a non-canonical surface of JAK2 (58, 59). The KIR of SOCS3 occludes the substrate-binding groove on JAK2. SIGNOR-255329 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT down-regulates phosphorylation Tyr317 TEQDLQLyCDFPNII 9606 BTO:0000007 19364823 YES 16705160:the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling. lperfetto Analysis of in vitro autophosphorylated jak2while cytokine receptor stimulation mediates the phosphorylation of both tyr317 and tyr637, these residues oppositely regulate jak2-dependent signaling: the mutation of tyr317 enhances jak2 function, suggesting a role for the phosphorylation of tyr317 in the inhibition of jak2. Conversely, mutation of tyr637 reduces jak2 signaling, suggesting a role for the phosphorylation of this residue in the activation of jak2. SIGNOR-236502 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity phosphorylation Tyr570 VRREVGDyGQLHETE 9606 21841788 YES lperfetto The jak2 jh2 domain functions as a negative regulator and is presumed to be a catalytically inactive pseudokinase, but the mechanism(s) for its inhibition of jak2 remains unknown. Here we show that jh2 is a dual-specificity protein kinase that phosphorylates two negative regulatory sites in jak2: ser523 and tyr570. SIGNOR-176058 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity phosphorylation Ser523 GVSDVPTsPTLQRPT 9606 21841788 YES lperfetto The jak2 jh2 domain functions as a negative regulator and is presumed to be a catalytically inactive pseudokinase, but the mechanism(s) for its inhibition of jak2 remains unknown. Here we show that jh2 is a dual-specificity protein kinase that phosphorylates two negative regulatory sites in jak2: ser523 and tyr570. SIGNOR-176054 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates phosphorylation Tyr966 QICKGMEyLGTKRYI 9606 BTO:0000007 20304997 YES lperfetto Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity SIGNOR-236290 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates phosphorylation Tyr221 IRAKIQDyHILTRKR 9606 BTO:0000007 15143187 YES lperfetto Autophosphorylation of jak2 on tyrosines 221 and 570 regulates its activity with phosphorylation of tyrosine 221 increasing kinase activity SIGNOR-236506 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates phosphorylation Tyr868 GSVEMCRyDPLQDNT 9606 BTO:0000007 20304997 YES lperfetto Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity SIGNOR-236298 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr637 KFGSLDTyLKKNKNC 9606 BTO:0000007 19364823 YES 16705160:The effect of Ser523 on Jak2 function was independent of Tyr570-mediated inhibition. lperfetto Analysis of in vitro autophosphorylated jak2while cytokine receptor stimulation mediates the phosphorylation of both tyr317 and tyr637, these residues oppositely regulate jak2-dependent signaling: the mutation of tyr317 enhances jak2 function, suggesting a role for the phosphorylation of tyr317 in the inhibition of jak2. Conversely, mutation of tyr637 reduces jak2 signaling, suggesting a role for the phosphorylation of this residue in the activation of jak2. SIGNOR-235885 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1007 VLPQDKEyYKVKEPG -1 9111318 YES Multiple autophosphorylation sites on Jak2, including Y1007 and Y1008. Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop. SIGNOR-251357 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr221 IRAKIQDyHILTRKR 9606 BTO:0000007 15143187 YES JAK2 is autophosphorylated on tyrosines 221 and 1007. tyrosines 221 and 570 in JAK2 may serve as regulatory sites in JAK2, with phosphorylation of tyrosine 221 increasing kinase activity and phosphorylation of tyrosine 570 decreasing kinase activity SIGNOR-251356 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT unknown phosphorylation Tyr1007 VLPQDKEyYKVKEPG -1 9111318 YES Within the Jak2 kinase domain, there is a region that has considerable sequence homology to the regulatory region of the insulin receptor and contains two tyrosines, Y1007 and Y1008, that are potential regulatory sites. Y1007 and Y1008 are sites of trans- or autophosphorylation in vivo and in in vitro kinase reactions. Mutation of Y1007, or both Y1007 and Y1008, to phenylalanine essentially eliminated kinase activity, whereas mutation of Y1008 to phenylalanine had no detectable effect on kinase activity SIGNOR-251358 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity phosphorylation Tyr570 VRREVGDyGQLHETE 9606 BTO:0000007 15143187 YES JAK2 is autophosphorylated on tyrosines 221 and 1007. tyrosines 221 and 570 in JAK2 may serve as regulatory sites in JAK2, with phosphorylation of tyrosine 221 increasing kinase activity and phosphorylation of tyrosine 570 decreasing kinase activity SIGNOR-251359 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr201 DQTPLAIyNSISYKT 9534 BTO:0000298 17027227 YES Site of Jak2 tyrosine autophosphorylation; namely, tyrosine 201. Jak2 tyrosine residue 201 was the principal mediator of SHP-2 binding as conversion of this tyrosine residue to phenylalanine abolished this interaction SIGNOR-251360 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr972 EYLGTKRyIHRDLAT 9606 BTO:0000007 20304997 YES lperfetto Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity SIGNOR-236294 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr813 NSLFTPDyELLTEND 9606 BTO:0000007 15121872 YES 16705160:The effect of Ser523 on Jak2 function was independent of Tyr570-mediated inhibition. lperfetto Tyrosine 813 is a site of jak2 autophosphorylation critical for activation of jak2 by sh2-b betawe show that phosphorylation of tyrosine 813 is required for the sh2 domain-containing adapter protein sh2-b beta to bind jak2 and to enhance the activity of jak2 and stat5b. SIGNOR-235910 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy FOXO1 protein Q12778 UNIPROT TRIM63 protein Q969Q1 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18612045 NO lperfetto Transcriptional reporter assays performed in both HepG2 and C2C12 cells demonstrate that the MuRF1 promoter is highly responsive to dexamethasone-activated glucocorticoid receptor (GR) and FoxO1 individually, while co-overexpression of GR and FoxO1 leads to a dramatic synergistic increase in reporter activity SIGNOR-235367 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy FOXO1 protein Q12778 UNIPROT TRIM63 protein Q969Q1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21798082 NO lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. SIGNOR-235712 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy FOXO1 protein Q12778 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 15109499 NO miannu The activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1 induction. IGF-1 treatment or AKT overexpression inhibits Foxo and atrogin-1 expression. SIGNOR-252069 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy FOXO1 protein Q12778 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21798082 NO lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. SIGNOR-236540 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy MSTN protein O14793 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 19357233 NO miannu In the current study, it was demonstrated that myostatin inhibits activation of Akt, in both myoblasts and myotubes. SIGNOR-255339 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy IL6 protein P05231 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity -1 8511589 NO lperfetto The biological functions of interleukin-6 (IL-6) are mediated through a signal-transducing component of the IL-6 receptor, gp130, which is associated with the ligand-occupied IL-6 receptor (IL-6R) protein. Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130. Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein. Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130. SIGNOR-238617 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy IL6 protein P05231 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity binding 9606 BTO:0001271 15895091 YES miannu A crystal structure of the ligand-binding domains of gp130 in complex with human interleukin-6 (il-6) and its a-receptor (il-6ralpha) revealed a hexameric architecture in which the gp130 membrane-distal regions were approximately 100 a apart, in contrast to the close apposition seen between short cytokine receptor complexes. SIGNOR-48041 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates activity binding 9606 18923185 YES miannu IL-6 and IL-11 are the only members of the family that signal via the induction of a gp130 homodimer after binding their specific -receptors, IL-6R and IL-11R. When IL-6 binds to the homodimerized IL-6Rα/gp130Rβ, it results in a signaling cascade that is initiated by the autophoshorylation and activation of JAK. SIGNOR-255324 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 23663276 YES milica In classical il-6 signaling, the cytokine first binds to the membrane-bound il-6 receptor (il-6r;cd126) that is induced to associate with a homodimer of gp130 which then transmits the intracellular signal. SIGNOR-202030 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 15895091 YES gcesareni We show that the augmentation of the il6 signal by recombinant il6 receptors (ril6r) delivery allows the functional recovery of phagocytes in a peritonitis mouse model. SIGNOR-137236 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 8676083 YES fspada We first observed that cultured mouse embryonic dorsal root ganglia exhibited dramatic neurite extension by simultaneous addition of il-6 and soluble il-6r (sil-6r), a complex that is known to interact with and activate a signal transducing receptor component, gp130 SIGNOR-42866 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy IL6 protein P05231 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates 10090 23531613 NO AMPK phosphorylation was increased nearly fourfold (Fig. 2C) with the high dose of IL-6 SIGNOR-255338 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy FOXO3 protein O43524 UNIPROT TRIM63 protein Q969Q1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 21798082 NO lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. SIGNOR-236551 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy FOXO3 protein O43524 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 15109499 NO miannu Constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers SIGNOR-252070 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy FOXO3 protein O43524 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 21798082 NO lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. SIGNOR-235715 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy FOXO3 protein O43524 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15109499 NO lperfetto Moreover, constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers. SIGNOR-232174 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy FBXO32 protein Q969P5 UNIPROT Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 10090 20871233 NO Atrogin-1, but not MuRF-1, was induced at both the gene and protein level as ApcMin/+ mice aged from 3 to 6 months of age, going from a pre-cachectic to a cachectic state. Atrogin-1 mRNA and protein levels were also elevated in ApcMin/+ mice when we over-expressed IL-6 in the circulation. SIGNOR-255341 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy FBXO32 protein Q969P5 UNIPROT Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 10090 11717410 NO Atrogin-1 is one of the few examples of an F-box protein or Ub-protein ligase (E3) expressed in a tissue-specific manner and appears to be a critical component in the enhanced proteolysis leading to muscle atrophy in diverse diseases SIGNOR-255342 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy FBXO32 protein Q969P5 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 BTO:0001103 20871233 NO Atrogin-1, but not MuRF-1, was induced at both the gene and protein level as ApcMin/+ mice aged from 3 to 6 months of age, going from a pre-cachectic to a cachectic state. Atrogin-1 mRNA and protein levels were also elevated in ApcMin/+ mice when we over-expressed IL-6 in the circulation. SIGNOR-255343 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy FBXO32 protein Q969P5 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 BTO:0001103 11717410 NO Atrogin-1 is one of the few examples of an F-box protein or Ub-protein ligase (E3) expressed in a tissue-specific manner and appears to be a critical component in the enhanced proteolysis leading to muscle atrophy in diverse diseases SIGNOR-255344 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy CEBPD protein P49716 UNIPROT MSTN protein O14793 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 24011072 NO miannu To identify whether p-Stat3 acts through C/EBPŒ¥ to stimulate myostatin, we knocked down C/EBPŒ¥ using siRNA. In this case, the IL-6-induced increase in myostatin expression was blocked when C/EBPŒ¥was suppressed even though p-Stat3 was increased SIGNOR-255332 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy CASP3 protein P42574 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity cleavage -1 10579725 YES lperfetto P53 can inhibit the survival function of integrins by inducing the caspase-dependent cleavage and inactivation of the serine/threonine kinase akt/pkb;the involvement of caspase 3 in akt/pkb regulation was indicated by the ability of z-devd-fmk, a caspase 3 inhibitor, to block the alpha6beta4-associated reduction in akt/pkb levels in vivo, and by the ability of recombinant caspase 3 to promote the cleavage of akt/pkb in vitro SIGNOR-72677 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy CASP3 protein P42574 UNIPROT Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 10090 25787076 NO miannu The UPS by itself degrades actomyosin and myofibrillar proteins slowly, but when caspase-3 is activated, it cleaves actomyosin and the myofibrillar proteins to provide substrates for degradation in the UPS . Caspase-3 also can cleave specific subunits of the 19 S proteasome particle, which stimulates the proteolytic activity of the 26S proteasome[...] These results indicate that caspase-3 participates in the muscle proteolysis that is present in tumor-bearing mice. SIGNOR-255337 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy CASP3 protein P42574 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 25787076 NO miannu The UPS by itself degrades actomyosin and myofibrillar proteins slowly, but when caspase-3 is activated, it cleaves actomyosin and the myofibrillar proteins to provide substrates for degradation in the UPS . Caspase-3 also can cleave specific subunits of the 19 S proteasome particle, which stimulates the proteolytic activity of the 26S proteasome[...] These results indicate that caspase-3 participates in the muscle proteolysis that is present in tumor-bearing mice SIGNOR-255336 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy TRIM63 protein Q969Q1 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates activity 10090 25549588 NO areggio Muscle-specific ubiq- uitin ligases, muscle-specific RING-finger 1 (MURF1; also known as TRIM63)12 and atrogin 1 (also known as MAFBX), are markedly induced in almost all types of atrophy. SIGNOR-254993 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy STAT3 protein P40763 UNIPROT CASP3 protein P42574 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 25787076 NO miannu We determined that Stat3 activation increases caspase-3 expression in C2C12 cells. SIGNOR-255335 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy STAT3 protein P40763 UNIPROT CEBPD protein P49716 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 24011072 NO miannu To assess whether Stat3 affects C/EBPŒ¥ expression, we co-transfected C2C12 myoblasts with a plasmid expressing a C/EBPŒ¥promoter-driven luciferase plus a lentivirus expressing the constitutively active Stat3C-GFP. Overexpression of Stat3C increased C/EBPŒ¥promoter activity compared to that in lentivirus expressing GFP control SIGNOR-255333 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy STAT3 protein P40763 UNIPROT CEBPD protein P49716 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 25787076 NO miannu P-Stat3 stimulates C/EBPδ expression and activity, which increases myostatin and MAFbx/Atrogin-1 and MuRF-1. Both pathways result in protein losses in muscle. SIGNOR-255334 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy STAT3 protein P40763 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 22669242 NO miannu Thus we infected C2C12 myofibers with a recombinant adenovirus expressing a mutant, constitutively activated STAT3 (cSTAT3) known to possess increased DNA binding/transcriptional activity. Consistent with wasting, atrogin-1 expression was also markedly increased (Fig. 3A). Thus STAT3 activation is by itself sufficient to induce muscle fiber wasting in cell culture. SIGNOR-255331 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy STAT3 protein P40763 UNIPROT SOCS3 protein O14543 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11159537 NO miannu STAT3-mediated constitutive expression of SOCS-3 in cutaneous T-cell lymphoma. SIGNOR-253050 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy STAT3 protein P40763 UNIPROT SOCS3 protein O14543 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12565872 YES We also found that the wild type SOCS-3 promoter construct has significantly greater activity in non-small-cell lung cancer cell lines than in normal cells in accordance with STAT3 disregulation in these cells SIGNOR-253583 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy IL6R protein P08887 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 23663276 YES milica In classical il-6 signaling, the cytokine first binds to the membrane-bound il-6 receptor (il-6r;cd126) that is induced to associate with a homodimer of gp130 which then transmits the intracellular signal. SIGNOR-202033 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy IL6R protein P08887 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 BTO:0000785 11238858 YES gcesareni Part of the receptor for interleukin 6. Binds to il6 with low affinity, but does not transduce a signal. Signal activation necessitate an association with il6st. Activation may lead to the regulation of the immune response, acute-phase reactions and hematopoiesis. SIGNOR-105504 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy IL6R protein P08887 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation 9606 23869758 YES miannu On binding of IL-6 to its receptor IL-6R, JAK2 is phosphorylated, then STAT3 is phosphorylated by JAK2 SIGNOR-254405 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy IL6ST protein P40189 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity phosphorylation Ser661 NVPDPSKsHIAQWSP -1 8511589 YES lperfetto The biological functions of interleukin-6 (IL-6) are mediated through a signal-transducing component of the IL-6 receptor, gp130, which is associated with the ligand-occupied IL-6 receptor (IL-6R) protein. Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130. Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein. Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130. SIGNOR-238625 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy IL6ST protein P40189 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity phosphorylation Ser659 WPNVPDPsKSHIAQW -1 8511589 YES lperfetto The biological functions of interleukin-6 (IL-6) are mediated through a signal-transducing component of the IL-6 receptor, gp130, which is associated with the ligand-occupied IL-6 receptor (IL-6R) protein. Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130. Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein. Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130. SIGNOR-238621 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy IL6ST protein P40189 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 9716487 YES lperfetto All IL-6-type cytokines recruit gp130to their receptot complexes They either signal via gp130 alone [8] or in combination with LIFR [9] or the recently cloned OSMR [10], which are all able to activate Jaks proteins. Two tyrosine residues at the corresponding positions of Jak2 (tyrosine-1007 and tyrosine-1008) were found to be phosphorylated, and a single mutation of tyrosine-1007 eliminated essentially all tyrosine kinase activity [59]. SIGNOR-238630 SIGNOR-MyoIL6ATR Myofiber: IL6 and atrophy IL6ST protein P40189 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1008 LPQDKEYyKVKEPGE 9606 9716487 YES lperfetto All IL-6-type cytokines recruit gp130to their receptot complexes They either signal via gp130 alone [8] or in combination with LIFR [9] or the recently cloned OSMR [10], which are all able to activate Jaks proteins. Two tyrosine residues at the corresponding positions of Jak2 (tyrosine-1007 and tyrosine-1008) were found to be phosphorylated, and a single mutation of tyrosine-1007 eliminated essentially all tyrosine kinase activity [59]. SIGNOR-238634 SIGNOR-Myostatin Myostatin AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 YES lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. These results indicate that phosphorylation by PKB/Akt negatively regulates FKHR1 by promoting export from the nucleus. SIGNOR-252346 SIGNOR-Myostatin Myostatin AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 YES lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-252347 SIGNOR-Myostatin Myostatin AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 21440011 YES lperfetto Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs SIGNOR-252348 SIGNOR-Myostatin Myostatin AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser319 TFRPRTSsNASTISG 9606 11237865 YES lperfetto The transcription factor, forkhead in rhabdomyosarcoma (fkhr), is phosphorylated at three amino acid residues (thr-24, ser-256 and ser-319) by protein kinase b (pkb)alpha.Fkhr (forkhead in rhabdomyosarcoma), afx (all1 fused gene from chromosome x) and fkhrl1 (fkhr-like 1) are phosphorylated directly by pkb in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus SIGNOR-252349 SIGNOR-Myostatin Myostatin AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 21798082 YES lperfetto Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b). SIGNOR-252352 SIGNOR-Myostatin Myostatin AKT proteinfamily SIGNOR-PF24 SIGNOR SMAD3 protein P84022 UNIPROT down-regulates binding 9606 15048128 YES gcesareni Pkb inhibits smad3 by preventing its phosphorylation, binding to smad4 and nuclear translocation. [...] Regulation of smad3 by pkb occurs through a kinase-activity-independent mechanism, resulting in a decrease in smad3-mediated transcription and protection of cells against tgf-beta-induced apoptosis. SIGNOR-252345 SIGNOR-Myostatin Myostatin PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 YES lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 SIGNOR-Myostatin Myostatin PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9534 9637919 YES lperfetto In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation. SIGNOR-58313 SIGNOR-Myostatin Myostatin PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation -1 9094314 YES gcesareni We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1) SIGNOR-243274 SIGNOR-Myostatin Myostatin PIK3CA protein P42336 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 YES AKT is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates (PIPs) with phosphate s at positions 3, 4 and 3,4,5 on the inositol ring miannu Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, which recruit akt to the plasma membrane through its pleckstrin homology (ph) domain, permitting its activation by pdks. SIGNOR-65409 SIGNOR-Myostatin Myostatin PIK3CA protein P42336 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24367090 YES AKT is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates (PIPs) with phosphate s at positions 3, 4 and 3,4,5 on the inositol ring miannu Insulin activation of phosphoinositide 3-kinase (pi3k) signaling regulates glucose homeostasis through the production of phosphatidylinositol 3,4,5-trisphosphate (pip3). The dual-specificity phosphatase and tensin homolog deleted on chromosome 10 (pten) blocks pi3k signaling by dephosphorylating pip3, and is inhibited through its interaction with phosphatidylinositol 3,4,5-trisphosphate-dependent rac exchanger 2 SIGNOR-147948 SIGNOR-Myostatin Myostatin PIK3CA protein P42336 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 12167717 YES lperfetto PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473, SIGNOR-244429 SIGNOR-Myostatin Myostatin SMAD2 protein Q15796 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates activity binding 9606 phosphorylation:Ser465;Ser467 SPSVRCSsMS;SVRCSSMs 11274206 YES gcesareni the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4 SIGNOR-235183 SIGNOR-Myostatin Myostatin SMAD3 protein P84022 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates activity binding 9606 9843571 YES gcesareni TGF-² treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. SIGNOR-235168 SIGNOR-Myostatin Myostatin PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser393 MQVSSSSsSHSLSAS 9606 10455013 YES lperfetto 3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity SIGNOR-235782 SIGNOR-Myostatin Myostatin PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser396 SSSSSSHsLSASDTG 9606 10455013 YES lperfetto 3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity SIGNOR-236764 SIGNOR-Myostatin Myostatin PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser25 VVLCSCPsPSMVRTQ 9606 10455013 YES lperfetto 3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity SIGNOR-236777 SIGNOR-Myostatin Myostatin PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser410 GLPQRSGsNIEQYIH 9606 10455013 YES lperfetto 3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity SIGNOR-236772 SIGNOR-Myostatin Myostatin PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT down-regulates quantity by destabilization phosphorylation Ser241 SKQARANsFVGTAQY -1 12177059 YES miannu PDK1 kinase activity is negatively regulated by binding to 14-3-3 through the PDK1 autophosphorylation site Ser-241. PDK1 binds to 14-3-3 in vivo and in vitro through the residues surrounding the autophosphorylation site Ser-241 and that the association is achieved only when Ser-241 has been phosphorylated SIGNOR-250077 SIGNOR-Myostatin Myostatin PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates activity phosphorylation Ser241 SKQARANsFVGTAQY 9606 10455013 YES lperfetto Pdk1 is itself phosphorylated in vivo and whether phosphorylation plays a role in regulating its activity/ phosphorylation of ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1 SIGNOR-236789 SIGNOR-Myostatin Myostatin PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates activity phosphorylation Ser241 SKQARANsFVGTAQY 9606 11481331 YES miannu In terms of the modulation of PDK1 activity by reversible phosphorylation, five pS sites have been identified on PDK1 in vivo, but only one of these sites, Ser-241 in the activation loop of PDK1, is essential for activity. It seems likely that PDK1 autophosphorylates itself on this residue. SIGNOR-250268 SIGNOR-Myostatin Myostatin PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 YES lperfetto The activation of PKBbeta and PKBamma by PDK11 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma) SIGNOR-244480 SIGNOR-Myostatin Myostatin PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10116 BTO:0000142 10226025 YES lperfetto Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown. SIGNOR-244421 SIGNOR-Myostatin Myostatin PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15743829 YES lperfetto 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt), SIGNOR-244469 SIGNOR-Myostatin Myostatin ACVR1B protein P36896 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation 10090 14517293 YES gcesareni ActRIIB, and then partners with a type I receptor, either activin receptor-like kinase 4 (ALK4 or ActRIB) or ALK5 (T²RI), to induce phosphorylation of Smad2/Smad3 and activate a TGF-²-like signaling pathway SIGNOR-235160 SIGNOR-Myostatin Myostatin ACVR1B protein P36896 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation 9606 11389842 YES Indirect_regulation of phosphorylation miannu Nodal Induces Smad Phosphorylation through ALK4 in a Cripto-Dependent Manner SIGNOR-251943 SIGNOR-Myostatin Myostatin ACVR1B protein P36896 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation 10090 14517293 YES gcesareni ActRIIB, and then partners with a type I receptor, either activin receptor-like kinase 4 (ALK4 or ActRIB) or ALK5 (T²RI), to induce phosphorylation of Smad2/Smad3 and activate a TGF-²-like signaling pathway SIGNOR-235157 SIGNOR-Myostatin Myostatin FST protein P19883 UNIPROT INHBA protein P08476 UNIPROT down-regulates activity binding 10090 BTO:0005787 24627466 YES lperfetto Follistatin (FST) is a member of the tissue growth factor β family and is a secreted glycoprotein that antagonizes many members of the family, including activin A, growth differentiation factor 11, and myostatin. |FST315-ΔHBS-Fc induced improvements in muscle repair after injury/atrophy by modulating the early inflammatory phase allowing for increased macrophage density, and Pax7-positive cells leading to an accelerated restoration of myofibers and muscle function. SIGNOR-251715 SIGNOR-Myostatin Myostatin FST protein P19883 UNIPROT INHBA protein P08476 UNIPROT down-regulates activity binding 9606 22037168 YES gcesareni Blocking activin action by pre-treatment with its binding protein, follistatin, modifies the inflammatory cytokine cascade, and reduces the severity of the subsequent inflammatory response and mortality SIGNOR-235134 SIGNOR-Myostatin Myostatin FST protein P19883 UNIPROT MSTN protein O14793 UNIPROT down-regulates activity binding 10090 11459935 YES gcesareni Binding of myostatin to Act RIIB could be inhibited by the activin-binding protein follistatin and, at higher concentrations, by the myostatin propeptide. T SIGNOR-235150 SIGNOR-Myostatin Myostatin FOXO1 protein Q12778 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 15109499 NO miannu The activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1 induction. IGF-1 treatment or AKT overexpression inhibits Foxo and atrogin-1 expression. SIGNOR-252069 SIGNOR-Myostatin Myostatin FOXO1 protein Q12778 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21798082 NO lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. SIGNOR-236540 SIGNOR-Myostatin Myostatin MSTN protein O14793 UNIPROT ACVR2B protein Q13705 UNIPROT up-regulates activity binding 10090 11459935 YES gcesareni The purified C-terminal myostatin dimer was capable of binding the activin type II receptors, Act RIIB and, to a lesser extent, Act RIIA SIGNOR-235153 SIGNOR-Myostatin Myostatin FBXO32 protein Q969P5 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001103 19319192 YES gcesareni Here we present evidence that mafbx targets myod for degradation in several models of skeletal muscle atrophy. SIGNOR-184861 SIGNOR-Myostatin Myostatin FBXO32 protein Q969P5 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 25096180 NO Muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx)/atrogin-1 were identified more than 10 years ago as two muscle-specific E3 ubiquitin ligases that are increased transcriptionally in skeletal muscle under atrophy-inducing conditions, making them excellent markers of muscle atrophy SIGNOR-252072 SIGNOR-Myostatin Myostatin ACVR2B protein Q13705 UNIPROT ACVR1B protein P36896 UNIPROT up-regulates activity phosphorylation Thr206 VQRTVARtIVLQEII 9606 8622651 YES miannu Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB. SIGNOR-235146 SIGNOR-Myostatin Myostatin MYOD1 protein P15172 UNIPROT FST protein P19883 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 15130492 NO lperfetto MyoD, CREB, and NFAT Mediate the Transcriptional Activation of the Follistatin Promoter Induced by TSA SIGNOR-251727 SIGNOR-Myostatin Myostatin IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1161 FGMTRDIyETDYYRK -1 8940173 YES miannu The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246248 SIGNOR-Myostatin Myostatin IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1161 FGMTRDIyETDYYRK 9606 7493944 YES lperfetto Insulin and insulin-like growth factor (igf-i) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor. SIGNOR-26582 SIGNOR-Myostatin Myostatin IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1166 DIYETDYyRKGGKGL -1 8940173 YES miannu The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246244 SIGNOR-Myostatin Myostatin IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1166 DIYETDYyRKGGKGL 9606 7493944 YES lperfetto Insulin and insulin-like growth factor (igf-i) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor. SIGNOR-26590 SIGNOR-Myostatin Myostatin IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1346 SFDERQPyAHMNGGR -1 8940173 YES miannu The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246260 SIGNOR-Myostatin Myostatin IGF1R protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr373 SEDDEDCyGNYDNLL -1 20044479 YES lperfetto IGF-1R Directly Interacts with and Phosphorylates PDK1 in Vitro SIGNOR-236548 SIGNOR-Myostatin Myostatin IGF1R protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr376 DEDCYGNyDNLLSQF 9606 20643654 YES lperfetto Previous studies indicate that optimal activation of PDK1 requires phosphorylation of Tyr373/376, and growth factor receptor activation leads to PDK1 recruitment to the plasma membrane, followed by sequential phosphorylation of Tyr9 and then Tyr373/376 SIGNOR-166714 SIGNOR-Myostatin Myostatin IGF1R protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr373 SEDDEDCyGNYDNLL 9606 20643654 YES lperfetto Previous studies indicate that optimal activation of PDK1 requires phosphorylation of Tyr373/376 (11, 12, 14, 17), and growth factor receptor activation leads to PDK1 recruitment to the plasma membrane, followed by sequential phosphorylation of Tyr9 and then Tyr373/376 SIGNOR-166710 SIGNOR-Myostatin Myostatin IGF1R protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr376 DEDCYGNyDNLLSQF 9606 20044479 YES lperfetto We have described that upon ligand binding, igf-1r directly interacts with and phosphorylates pdk1 at tyr373/376 SIGNOR-236544 SIGNOR-NeutroAM Neutrophils: Adhesion and migration SELPLG protein Q14242 UNIPROT SELP protein P16109 UNIPROT up-regulates binding 9606 BTO:0000130 23994464 YES apalma This steady-state rolling is primarily mediated by the interaction of endothelial P-selectins with their neutrophil glycoprotein counterreceptors, primarily PSGL-1. SIGNOR-255038 SIGNOR-NeutroAM Neutrophils: Adhesion and migration SELPLG protein Q14242 UNIPROT SELP protein P16109 UNIPROT up-regulates binding 9606 BTO:0000130;BTO:0000150;BTO:0000551 BTO:0000975 9129046 YES gcesareni The major ligand for p-selectin on leukocytes is p-selectin glycoprotein ligand-1 (PSGL-1) SIGNOR-47625 SIGNOR-NeutroAM Neutrophils: Adhesion and migration SELPLG protein Q14242 UNIPROT SELE protein P16581 UNIPROT up-regulates binding 9606 BTO:0000130 9024699 YES gcesareni PSGL-1 was shown to mediate rolling of human neutrophils on p- and e-selectin in vitro. SIGNOR-46330 SIGNOR-NeutroAM Neutrophils: Adhesion and migration SELE protein P16581 UNIPROT ITGAL protein P20701 UNIPROT up-regulates 9606 BTO:0000130 23994464 NO apalma This deceleration is due to the expression of E-selectins on the inflamed endothelium which provides increased number of binding sites for PSGL-1 and also triggers an intermediate-affinity conformational state of the beta2-integrin LFA-1 on neutrophils. SIGNOR-255968 SIGNOR-NeutroAM Neutrophils: Adhesion and migration ITGAM protein P11215 UNIPROT ICAM1 protein P05362 UNIPROT up-regulates binding 9606 23994464 YES apalma Before leaving the vessel lumen, neutrophils crawl on the endothelium, primarily using cell surface Mac-1 integrins binding to endothelial ICAM-1. SIGNOR-255041 SIGNOR-NeutroAM Neutrophils: Adhesion and migration ITGAL protein P20701 UNIPROT ICAM1 protein P05362 UNIPROT up-regulates binding 9606 BTO:0000130 23994464 YES apalma This leads to further neutrophil-endothelial cell interactions through the binding of LFA-1 to its endothelial counterreceptor ICAM-1 during the slow rolling phase SIGNOR-255040 SIGNOR-NeutroAM Neutrophils: Adhesion and migration ICAM1 protein P05362 UNIPROT Chemotaxis phenotype SIGNOR-PH93 SIGNOR up-regulates 9606 23994464 NO apalma Before leaving the vessel lumen, neutrophils crawl on the endothelium, primarily using cell surface Mac-1 integrins binding to endothelial ICAM-1. After finding the place for transmigration, neutrophils migrate to the interstitium through transcellular or paracellular routes and begin chemotaxing towards the site of infection/inflammation within the perivascular and interstitial space. SIGNOR-255042 SIGNOR-NeutroGPCR Neutrophils: G-protein-coupled receptor 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI ITPR1 protein Q14643 UNIPROT up-regulates activity chemical activation 9606 24646566 YES miannu The key event in activation of fluid secretion is an increase in intracellular [ca2+] ([ca2+]i) triggered by ip3-induced release of ca2+ from er via the ip3r. ip3rs determine the site of initiation and the pattern of [ca2+]i signal in the cell. SIGNOR-256239 SIGNOR-NeutroGPCR Neutrophils: G-protein-coupled receptor GPCR proteinfamily SIGNOR-PF33 SIGNOR GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 YES miannu Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-255006 SIGNOR-NeutroGPCR Neutrophils: G-protein-coupled receptor GPCR proteinfamily SIGNOR-PF33 SIGNOR GNAI1 protein P63096 UNIPROT up-regulates 9606 23994464 YES apalma Activation of those receptors triggers the dissociation of the GPCR-specific GŒ± subunit from the shared GŒ≤Œ≥ dimer and concomitant activation of various signal transduction pathways by both G-protein fragments SIGNOR-255009 SIGNOR-NeutroGPCR Neutrophils: G-protein-coupled receptor GPCR proteinfamily SIGNOR-PF33 SIGNOR GNB/GNG complex SIGNOR-C202 SIGNOR up-regulates activity binding 9606 23994464 YES miannu Instead, our current understanding is that the majority of GPCR signal transduction in neutrophils occurs through the G gamma/beta subunit. G-protein-coupled receptors in neutrophils primarily signal through the Gβγ heterodimer, activating two parallel pathways through PLCβ2/3 and PI3Kγ. SIGNOR-255007 SIGNOR-NeutroGPCR Neutrophils: G-protein-coupled receptor PI3K complex SIGNOR-C156 SIGNOR superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity 23994464 NO apalma The PI3Kγ pathway (but not PLCβ2/3) is required for chemotaxis of the cells while both pathways are required for GPCR-induced superoxide release SIGNOR-255011 SIGNOR-NeutroGPCR Neutrophils: G-protein-coupled receptor PI3K complex SIGNOR-C156 SIGNOR Chemotaxis phenotype SIGNOR-PH93 SIGNOR up-regulates 23994464 NO apalma The PI3Kγ pathway (but not PLCβ2/3) is required for chemotaxis of the cells while both pathways are required for GPCR-induced superoxide release SIGNOR-255012 SIGNOR-NeutroGPCR Neutrophils: G-protein-coupled receptor GNB/GNG complex SIGNOR-C202 SIGNOR PLCB2 protein Q00722 UNIPROT up-regulates 23994464 YES apalma However, it was later shown that other PLCβ isoforms (particularly PLCβ2 and PLCβ3) can also be directly activated by Gβγ subunits SIGNOR-255015 SIGNOR-NeutroGPCR Neutrophils: G-protein-coupled receptor GNB/GNG complex SIGNOR-C202 SIGNOR PLCB3 protein Q01970 UNIPROT up-regulates 23994464 YES apalma However, it was later shown that other PLCβ isoforms (particularly PLCβ2 and PLCβ3) can also be directly activated by Gβγ subunits SIGNOR-255016 SIGNOR-NeutroGPCR Neutrophils: G-protein-coupled receptor GNB/GNG complex SIGNOR-C202 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates 23994464 YES apalma Similar to PLCβ activation, PI3K-activation by neutrophil GPCRs also occurs primarily through Gβγ subunits, through the unique PI3Kγ isoform which is directly activated by Gβγ dimers SIGNOR-255010 SIGNOR-NeutroGPCR Neutrophils: G-protein-coupled receptor PLCB3 protein Q01970 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate(6-) smallmolecule CHEBI:203600 ChEBI up-regulates quantity chemical modification 9606 23994464 YES apalma The first phase of this signal is likely mediated by phospholipase C≈í‚⧠(PLC≈í‚â§) enzymes leading to the generation of IP3 and concomitant release of Ca2+ from intracellular stores SIGNOR-255018 SIGNOR-NeutroGPCR Neutrophils: G-protein-coupled receptor PLCB3 protein Q01970 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity 23994464 NO apalma The PI3Kγ pathway (but not PLCβ2/3) is required for chemotaxis of the cells while both pathways are required for GPCR-induced superoxide release SIGNOR-255014 SIGNOR-NeutroGPCR Neutrophils: G-protein-coupled receptor ITPR1 protein Q14643 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity chemical modification 9606 24646566 YES miannu The key event in activation of fluid secretion is an increase in intracellular [ca2+] ([ca2+]i) triggered by ip3-induced release of ca2+ from er via the ip3r. ip3rs determine the site of initiation and the pattern of [ca2+]i signal in the cell. SIGNOR-256238 SIGNOR-NeutroGPCR Neutrophils: G-protein-coupled receptor GNAI1 protein P63096 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI down-regulates 9606 23994464 NO apalma The G alpha I subunit inhibits adenylyl cyclase activity and therefore reduces cytoplasmic cAMP levels SIGNOR-255008 SIGNOR-NeutroGPCR Neutrophils: G-protein-coupled receptor GNB1 protein P62873 UNIPROT PLCB2 protein Q00722 UNIPROT up-regulates binding 9606 1465133 YES gcesareni Activation of plc-beta 2 by beta gamma subunits may be an important mechanism by which pertussis toxin-sensitive g proteins stimulate plc. SIGNOR-19447 SIGNOR-NeutroGPCR Neutrophils: G-protein-coupled receptor GNB1 protein P62873 UNIPROT GNB/GNG complex SIGNOR-C202 SIGNOR form complex binding 9606 23994464 YES apalma Instead, our current understanding is that the majority of GPCR signal transduction in neutrophils occurs through the GŒ≤Œ≥ subunit SIGNOR-255004 SIGNOR-NeutroGPCR Neutrophils: G-protein-coupled receptor GNB1 protein P62873 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000938 16537363 YES gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt SIGNOR-252679 SIGNOR-NeutroGPCR Neutrophils: G-protein-coupled receptor GNG2 protein P59768 UNIPROT GNB/GNG complex SIGNOR-C202 SIGNOR form complex binding 9606 23994464 YES apalma Instead, our current understanding is that the majority of GPCR signal transduction in neutrophils occurs through the GŒ≤Œ≥ subunit SIGNOR-255005 SIGNOR-NeutroGPCR Neutrophils: G-protein-coupled receptor GNG2 protein P59768 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 17419683 YES gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt. SIGNOR-252682 SIGNOR-NeutroGPCR Neutrophils: G-protein-coupled receptor GNG2 protein P59768 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000938 16537363 YES gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt. SIGNOR-252683 SIGNOR-NeutroGPCR Neutrophils: G-protein-coupled receptor PLCB2 protein Q00722 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate(6-) smallmolecule CHEBI:203600 ChEBI up-regulates quantity chemical modification 9606 23994464 YES apalma The first phase of this signal is likely mediated by phospholipase C≈í‚⧠(PLC≈í‚â§) enzymes leading to the generation of IP3 and concomitant release of Ca2+ from intracellular stores SIGNOR-255017 SIGNOR-NeutroGPCR Neutrophils: G-protein-coupled receptor PLCB2 protein Q00722 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity 23994464 NO apalma The PI3Kγ pathway (but not PLCβ2/3) is required for chemotaxis of the cells while both pathways are required for GPCR-induced superoxide release SIGNOR-255013 SIGNOR-OstCAL Osteoblast: Osteocalcin transcriptional regulation RUNX2/EP300 complex SIGNOR-C211 SIGNOR BGLAP protein P02818 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002648 12697832 NO Giulio Giuliani In agreement with our studies in ROS 17/2.8 cells, coexpression of p300 and Runx2/Cbfa1 resulted in marked enhancement of the OC promoter activity, further indicating that both factors cooperate to stimulate this promoter. SIGNOR-255420 SIGNOR-OstCAL Osteoblast: Osteocalcin transcriptional regulation RUNX2 protein Q13950 UNIPROT BGLAP protein P02818 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11331591 NO gcesareni Tgf-beta inhibited the expression of the cbfa1 and osteocalcin genes, whose expression is controlled by cbfa1 in osteoblast-like cell lines. This inhibition was mediated by smad3, which interacts physically with cbfa1 and represses its transcriptional activity at the cbfa1-binding ose2 promoter sequence SIGNOR-107160 SIGNOR-OstCAL Osteoblast: Osteocalcin transcriptional regulation RUNX2 protein Q13950 UNIPROT BGLAP protein P02818 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004958; BTO:0002648 9182762 NO Giulio Giuliani Indeed, we identified Osf2/Cbfa1 binding sites in the promoter of four genes expressed only (the Osteocalcin genes) or highly (Œ±1(I) collagen, Bsp, and Osteopontin) in osteoblasts. Each of these elements was able to bind Osf2/Cbfa1. SIGNOR-255408 SIGNOR-OstCAL Osteoblast: Osteocalcin transcriptional regulation RUNX2 protein Q13950 UNIPROT SP7 protein Q8TDD2 UNIPROT up-regulates transcriptional regulation 10090 16574347 NO Giulio Giuliani Osx promoter activity was up-regulated by 2 fold after Runx2 over-expression in ATDC5 cells. Osx Is Phosphorylated by p38 at Ser-73 and Ser-77 SIGNOR-255410 SIGNOR-OstCAL Osteoblast: Osteocalcin transcriptional regulation RUNX2 protein Q13950 UNIPROT RUNX2/EP300 complex SIGNOR-C211 SIGNOR form complex binding 10116 BTO:0002648 12697832 YES Giulio Giuliani More interestingly, the bone-specific transcriptionfactor Runx2/Cbfa1 is present in the immunoprecipitated material, strongly indicating that in osteoblastic cells expressing OC, p300 and Runx2/Cbfa1 are components of the same nuclear protein complex. SIGNOR-255419 SIGNOR-OstCAL Osteoblast: Osteocalcin transcriptional regulation RUNX2 protein Q13950 UNIPROT Osteoblast_differentiation phenotype SIGNOR-PH9 SIGNOR up-regulates 10090 9182762 NO gcesareni Osf2/cbfa1 as an osteoblast-specific transcription factor and as a regulator of osteoblast differentiation SIGNOR-48940 SIGNOR-OstCAL Osteoblast: Osteocalcin transcriptional regulation SP7 protein Q8TDD2 UNIPROT BGLAP protein P02818 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004058; BTO:0000165 11792318 NO Giulio Giuliani To test whether Osx could activate typical osteoblast genes, we transfected an Osx expressing vector into both C2C12 and C3H10T1/2 cells. Our results showed that Osx produced an induction of osteocalcin RNA in both cell types. SIGNOR-255409 SIGNOR-OstCAL Osteoblast: Osteocalcin transcriptional regulation SP7 protein Q8TDD2 UNIPROT Osteoblast_differentiation phenotype SIGNOR-PH9 SIGNOR up-regulates 10090 11792318 NO Giulio Giuliani Our results established that the novel transcription factor Osx is required for osteoblast differentiation and hence for bone formation. SIGNOR-255449 SIGNOR-OstCAL Osteoblast: Osteocalcin transcriptional regulation DLX5 protein P56178 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22298955 NO gcesareni Dlx5 can drive runx2 expression and osteogenic differentiation in developing cranial suture mesenchyme , indicat-ing that dlx5 can work as an upstream gene of runx2. SIGNOR-195576 SIGNOR-OstCAL Osteoblast: Osteocalcin transcriptional regulation DLX5 protein P56178 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17335796 NO gcesareni Dlx5 can drive runx2 expression and osteogenic differentiation in developing cranial suture mesenchyme. SIGNOR-153454 SIGNOR-OstCAL Osteoblast: Osteocalcin transcriptional regulation DLX5 protein P56178 UNIPROT Osteoblast_differentiation phenotype SIGNOR-PH9 SIGNOR up-regulates 10090 12000792 NO Giulio Giuliani In conclusion, Dlx5 and Dlx6 are dynamic regulators of mammalian development, which are absolutely required for proper craniofacial and skeletal development and which display overlapping genetic functions in all tissues in which they are expressed. In addition, they appear to act as essential regulators of chondrogenesis and osteogenesis. SIGNOR-255450 SIGNOR-OsteoBMP Osteoblast: BMP SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR form complex binding 9606 20957627 YES lperfetto Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus. SIGNOR-255838 SIGNOR-OsteoBMP Osteoblast: BMP SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR DLX5 protein P56178 UNIPROT up-regulates transcriptional regulation 10090 BTO:0000165 12815054 NO ggiuliani Over-expression of Smad1 or Smad5, mediators of BMP-signaling, also induced Dlx5 expression even in the absence of BMP-2 treatment concomitant with positive ALP staining SIGNOR-255837 SIGNOR-OsteoBMP Osteoblast: BMP SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates activity binding 9606 BTO:0000567 15573378 YES ggiuliani The Runx2 WT and deletion constructs (1 √¢‚Ǩ‚Äú495, 1√¢‚Ǩ‚Äú464, and 1√¢‚Ǩ‚Äú432) all physically interact with the BMP2 responsive Smad 1 SIGNOR-255834 SIGNOR-OsteoBMP Osteoblast: BMP SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates transcriptional regulation 10090 BTO:0000165 11073979 NO ggiuliani As shown in Fig. 8A, overexpression of Smad5 by itself induced Runx2 expression even in the absence of BMP-2 (lane 5). Western blot analysis also confirmed the induced level of Runx2 protein in C2C12-Sm5 cells (Fig. 8B) SIGNOR-255835 SIGNOR-OsteoBMP Osteoblast: BMP SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates transcriptional regulation 9606 27563484 NO ggiuliani Smad1/5/8-Smad4 complex transcribed Runx2 expression, as they complex with Runx2 to initiate other osteoblast gene expression. SIGNOR-255836 SIGNOR-OsteoBMP Osteoblast: BMP RUNX2 protein Q13950 UNIPROT SP7 protein Q8TDD2 UNIPROT up-regulates transcriptional regulation 10090 16574347 NO Giulio Giuliani Osx promoter activity was up-regulated by 2 fold after Runx2 over-expression in ATDC5 cells. Osx Is Phosphorylated by p38 at Ser-73 and Ser-77 SIGNOR-255410 SIGNOR-OsteoBMP Osteoblast: BMP RUNX2 protein Q13950 UNIPROT Osteoblast_differentiation phenotype SIGNOR-PH9 SIGNOR up-regulates 10090 9182762 NO gcesareni Osf2/cbfa1 as an osteoblast-specific transcription factor and as a regulator of osteoblast differentiation SIGNOR-48940 SIGNOR-OsteoBMP Osteoblast: BMP SP7 protein Q8TDD2 UNIPROT Osteoblast_differentiation phenotype SIGNOR-PH9 SIGNOR up-regulates 10090 11792318 NO Giulio Giuliani Our results established that the novel transcription factor Osx is required for osteoblast differentiation and hence for bone formation. SIGNOR-255449 SIGNOR-OsteoBMP Osteoblast: BMP SMAD4 protein Q13485 UNIPROT SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR form complex binding 9606 20957627 YES lperfetto Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus. SIGNOR-255832 SIGNOR-OsteoBMP Osteoblast: BMP BMPR1A protein P36894 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 10090 10712517 YES gcesareni Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors SIGNOR-75652 SIGNOR-OsteoBMP Osteoblast: BMP BMPR1A protein P36894 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity 10090 8533096 NO ggiuliani We also examined whether TAK1 was activated by bone morphogenetic protein (BMP). BMP-4 also stimulated TAK1 activity in a time- and dose-dependent manner SIGNOR-255815 SIGNOR-OsteoBMP Osteoblast: BMP BMPR1A protein P36894 UNIPROT SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000165;BTO:0002974; BTO:0002809 9442019 YES ggiuliani In this study, we isolated human Smad5 and found that Smad5 was involved in BMP-2 signaling cascades, which mediate the bone-inducing effects of BMP-2. Smad5 was directly serine-phosphorylated by BMPIR through a physical interaction. The activated Smad5 subsequently formed a complex with DPC4, and this complex was then translocated to the nucleus. SIGNOR-255830 SIGNOR-OsteoBMP Osteoblast: BMP BMPR1A protein P36894 UNIPROT SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR up-regulates activity phosphorylation 10090 BTO:0004058 19620713 YES ggiuliani The expression of CA-BMPr1A and CA-BMPr1B mRNA was confirmed by RT-PCR using appropriate primers to distinguish expression of the constitutively active receptors from endogenous BMP receptors; specific antibodies for these receptors were not available. However, the functional effects of their expression, i.e., phosphorylation of Smad1/5/8 and p38 MAPK, verify overexpression of the constitutively active receptors (Fig. 3B). Thus, their overexpression provoked a substantial rise in the phosphorylation of Smad1/5/8 and p38 MAPK, known downstream phosphorylated intermediates in the BMP signaling pathway (Fig. 3B) (16, 17). SIGNOR-255831 SIGNOR-OsteoBMP Osteoblast: BMP DLX5 protein P56178 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22298955 NO gcesareni Dlx5 can drive runx2 expression and osteogenic differentiation in developing cranial suture mesenchyme , indicat-ing that dlx5 can work as an upstream gene of runx2. SIGNOR-195576 SIGNOR-OsteoBMP Osteoblast: BMP DLX5 protein P56178 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17335796 NO gcesareni Dlx5 can drive runx2 expression and osteogenic differentiation in developing cranial suture mesenchyme. SIGNOR-153454 SIGNOR-OsteoBMP Osteoblast: BMP DLX5 protein P56178 UNIPROT Osteoblast_differentiation phenotype SIGNOR-PH9 SIGNOR up-regulates 10090 12000792 NO Giulio Giuliani In conclusion, Dlx5 and Dlx6 are dynamic regulators of mammalian development, which are absolutely required for proper craniofacial and skeletal development and which display overlapping genetic functions in all tissues in which they are expressed. In addition, they appear to act as essential regulators of chondrogenesis and osteogenesis. SIGNOR-255450 SIGNOR-OsteoBMP Osteoblast: BMP MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Thr180 RHTDDEMtGYVATRW 9606 8622669 YES lperfetto Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. SIGNOR-40349 SIGNOR-OsteoBMP Osteoblast: BMP MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 8622669 YES lperfetto Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. SIGNOR-40353 SIGNOR-OsteoBMP Osteoblast: BMP MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000130;BTO:0000801;BTO:0000876 7535770 YES lperfetto Recently, two map kinase kinases (mkk3 and mkk4) that activate p38 map kinase have been identified. the mechanism of p38 activation is mediated by dual phosphorylation on thr-180 and tyr-182. SIGNOR-236103 SIGNOR-OsteoBMP Osteoblast: BMP MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 8622669 YES lperfetto Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. MKK3 is therefore a specific activator of p38 MAP kinase that is independent of the JNK and ERK signaling pathways. SIGNOR-40356 SIGNOR-OsteoBMP Osteoblast: BMP MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9534 7839144 YES lperfetto Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. SIGNOR-232156 SIGNOR-OsteoBMP Osteoblast: BMP MAP3K7 protein O43318 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 11460167 YES lperfetto The activity of tak1 to phosphorylate mkk6, which activates the jnk-p38 kinase pathway, is directly regulated by k63-linked polyubiquitination SIGNOR-109497 SIGNOR-OsteoBMP Osteoblast: BMP MAP3K7 protein O43318 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 21902831 YES lperfetto Tak1 can phosphorylate and activate map kinase kinase 3/6 (mkk3/6), and numerous studies have demonstrated a requirement for mkk3/6 activity in the initiation of myoblast differentiation, again in a p38-dependent manner. SIGNOR-236145 SIGNOR-OsteoBMP Osteoblast: BMP MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Ser192 HMTNNKGsAAWMAPE -1 20538596 YES lperfetto Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation. SIGNOR-232153 SIGNOR-OsteoBMP Osteoblast: BMP MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Ser192 HMTNNKGsAAWMAPE 9606 10702308 YES lperfetto A mutant of TAK1 that lacks kinase activity is not phosphorylated either following IL-1 treatment or when coexpressed with TAB1, indicating that TAK1 phosphorylation is due to autophosphorylation. Furthermore, mutation to alanine of a conserved serine residue (Ser-192) in the activation loop between kinase domains VII and VIII abolishes both phosphorylation and activation of TAK1. These results suggest that IL-1 and ectopic expression of TAB1 both activate TAK1 via autophosphorylation of Ser-192. SIGNOR-235758 SIGNOR-OsteoBMP Osteoblast: BMP MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Thr184 GTACDIQtHMTNNKG -1 20538596 YES lperfetto Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation. SIGNOR-227544 SIGNOR-OsteoBMP Osteoblast: BMP MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Thr178 LKICDFGtACDIQTH -1 20538596 YES lperfetto Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation. SIGNOR-227536 SIGNOR-OsteoBMP Osteoblast: BMP MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Thr187 CDIQTHMtNNKGSAA -1 20538596 YES lperfetto Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation. SIGNOR-227540 SIGNOR-OsteoBMP Osteoblast: BMP MAP3K7 protein O43318 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000222 21902831 YES lperfetto TAK1 can phosphorylate and activate MAP kinase kinase 3/6 (MKK3/6), and numerous studies have demonstrated a requirement for MKK3/6 activity in the initiation of myoblast differentiation, again in a p38-dependent manner. SIGNOR-236093 SIGNOR-OsteoBMP Osteoblast: BMP MAP3K7 protein O43318 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 10090 17299140 YES lperfetto Taken together, our data indicate that TAK1 and TAB1 play a pivotal role as upstream signal transducers activating the MKK3-p38 MAPK signaling cascade that leads to the induction of type I collagen expression by TGF-beta(1). In addition, our findings also suggest that TAK1 has a novel function in regulation of the steady-state protein levels of MKK3 and p38 MAPK. SIGNOR-42402 SIGNOR-OsteoBMP Osteoblast: BMP BMP2 protein P12643 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates activity binding 9534 SIGNOR-C29 7791754 YES lperfetto Under our assay conditions, bmp-2 binds better to bmpr-ii in combination with actr-i or bmpr-ib than in combination with bmpr-ia SIGNOR-144101 SIGNOR-OsteoBMP Osteoblast: BMP BMP2 protein P12643 UNIPROT BMP2 protein P12643 UNIPROT up-regulates binding 9606 BTO:0000887 11178121 YES lperfetto Bmps are dimeric proteins with a single interchain disulfide bond. The dimeric conformation is an absolute requirement for the biological action and interaction with receptors SIGNOR-236166 SIGNOR-OsteoBMP Osteoblast: BMP BMP2 protein P12643 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates activity binding -1 18937504 YES ggiuliani Here we report the high-resolution NMR structure of BMPR-IA ECD in solution, revealing that a large part of the ligand-binding epitope is unfolded and flexible before formation of the complex. The binding beta4beta5 loop of BMPR-IA passes through a structural rearrangement upon BMP-2 binding. SIGNOR-255771 SIGNOR-OsteoBMP Osteoblast: BMP BMPR2 protein Q13873 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates binding 9534 7791754 YES fspada Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor. SIGNOR-33440 SIGNOR-OsteoBMP Osteoblast: BMP BMPR2 protein Q13873 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C29 SIGNOR-C29 18756288 YES gcesareni Bmp ligands bind to the bmp receptors bmpr1 and bmpr2, and bmpr2 then phosphorylates and activates bmpr1. SIGNOR-180545 SIGNOR-OsteoBMP Osteoblast: BMP BMPR2 protein Q13873 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates activity binding 10090 10712517 YES ggiuliani Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known BMP type I receptors (BR-Ia and BR-Ib) and the BMP type II receptor (BR-II). Coimmunoprecipitation studies detected the formation of heteromeric and homomeric complexes among all the BMP receptor types even in the absence of ligand. SIGNOR-255781 SIGNOR-OsteoBMP Osteoblast: BMP MAPK14 protein Q16539 UNIPROT DLX5 protein P56178 UNIPROT up-regulates activity phosphorylation Ser34 MHHPSQEsPTLPESS 10090 18056716 YES ggiuliani We show that Dlx5 is a novel substrate for p38 MAPK in vitro and in vivo and that Ser-34 and Ser-217 are the sites phosphorylated by p38 SIGNOR-255792 SIGNOR-OsteoBMP Osteoblast: BMP MAPK14 protein Q16539 UNIPROT SP7 protein Q8TDD2 UNIPROT up-regulates activity phosphorylation 10090 20682789 YES ggiuliani We therefore propose that Osterix binds to Sp1 sequences on target gene promoters and that its phosphorylation by p38 enhances recruitment of coactivators to form transcriptionally active complexes SIGNOR-255791 SIGNOR-OsteoBMP Osteoblast: BMP MAPK14 protein Q16539 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates activity phosphorylation 10090 20551513 YES ggiuliani Mechanistic analysis revealed that the TAK1–MKK3/6–p38 MAPK axis phosphorylated Runx2, promoting its association with the coactivator CREB-binding protein (CBP), which was required to regulate osteoblast genetic programs. These findings reveal an in vivo function for p38β and establish that MAPK signaling is essential for bone formation in vivo. SIGNOR-255777 SIGNOR-OsteoBMP Osteoblast: BMP MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000298 8974401 YES lperfetto A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively. SIGNOR-236116 SIGNOR-OsteoBMP Osteoblast: BMP MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Thr180 RHTDDEMtGYVATRW 9534 8622669 YES lperfetto These data indicate that mkk6 phosphorylates p38 map kinase on thr-180 and tyr-182, the sites of phosphorylation that activate p38 map kinase SIGNOR-40423 SIGNOR-OsteoBMP Osteoblast: BMP MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr182 TDDEMTGyVATRWYR 9534 8622669 YES lperfetto These data indicate that mkk6 phosphorylates p38 map kinase on thr-180 and tyr-182, the sites of phosphorylation that activate p38 map kinase SIGNOR-40427 SIGNOR-OsteoBMP Osteoblast: BMP MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 10480932 YES lperfetto We have found that p38 mitogen-activated protein kinase, and its direct activator MKK6 are rapidly activated in response to TGF-beta. SIGNOR-70607 SIGNOR-OsteoBMP Osteoblast: BMP MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 20551513 YES ggiuliani Expression of a constitutively active mutant of MKK6 (MKK6-glu) (39), but not a kinase-inactive mutant of MKK6 (MKK6-K82A) (39), strongly promoted human MSC differentiation to osteoblasts as shown by increased ALP activity and extracellular matrix mineralization (Figure 4E). Furthermore, MKK6-glu‚Äìexpressing osteoblasts were treated with inhibitors of p38, JNK, and MEK (Figure 4F). Only treatment with the p38 inhibitor SB203580 blocked the effects of MKK6-glu. SIGNOR-255780 SIGNOR-OsteoTGFB Osteoblast: TGF beta TRAF6 protein Q9Y4K3 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity ubiquitination Lys34 NFEEIDYkEIEVEEV 9606 18758450 YES lperfetto Intriguingly, TGF-beta-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6. SIGNOR-236071 SIGNOR-OsteoTGFB Osteoblast: TGF beta RUNX2 protein Q13950 UNIPROT SP7 protein Q8TDD2 UNIPROT up-regulates transcriptional regulation 10090 16574347 NO Giulio Giuliani Osx promoter activity was up-regulated by 2 fold after Runx2 over-expression in ATDC5 cells. Osx Is Phosphorylated by p38 at Ser-73 and Ser-77 SIGNOR-255410 SIGNOR-OsteoTGFB Osteoblast: TGF beta RUNX2 protein Q13950 UNIPROT Osteoblast_differentiation phenotype SIGNOR-PH9 SIGNOR up-regulates 10090 9182762 NO gcesareni Osf2/cbfa1 as an osteoblast-specific transcription factor and as a regulator of osteoblast differentiation SIGNOR-48940 SIGNOR-OsteoTGFB Osteoblast: TGF beta TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity binding 9606 22326956 YES lperfetto TGF-beta signaling mediates a wide range of biological activities in development and disease. TGF-beta ligands signal through heterodimeric type I and type II receptors (TGF-beta receptor type I [TbetaRI, also known as ALK5 and TGFBR1] and TbetaRII) that are members of the serine/threonine kinase family. SIGNOR-196022 SIGNOR-OsteoTGFB Osteoblast: TGF beta TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity binding 9606 22326956 YES giulio giuliani In Tgfbr2fl/fl control MEPM cells, radioactive TGF-β2 ligands (12.5 kDa) bind to TβRI (53 kDa), TβRII (70 kDa), and TβRIII (100–200 kDa, highly glycosylated molecule) and form the ligand-receptor complexes of TβRI::TGF-β2 (65.5 kDa), TβRII::TGF-β2 (82.5 kDa), and TβRIII::TGF-β2 (112.5–212.5 kDa) SIGNOR-255960 SIGNOR-OsteoTGFB Osteoblast: TGF beta TGFB1 protein P01137 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates activity binding 9534 BTO:0004055 1310899 YES lperfetto A cdna encoding the tgf-beta type ii receptor protein has been isolated by an expression cloning strategy. The cloned cdna, when transfected into cos cells, leads to overexpression of an approximately 80 kd protein that specifically binds radioiodinated tgf-beta 1. Excess tgf-beta 1 competes for binding of radioiodinated tgf-beta 1 in a dose-dependent manner and is more effective than tgf-beta 2. SIGNOR-236080 SIGNOR-OsteoTGFB Osteoblast: TGF beta SP7 protein Q8TDD2 UNIPROT Osteoblast_differentiation phenotype SIGNOR-PH9 SIGNOR up-regulates 10090 11792318 NO Giulio Giuliani Our results established that the novel transcription factor Osx is required for osteoblast differentiation and hence for bone formation. SIGNOR-255449 SIGNOR-OsteoTGFB Osteoblast: TGF beta TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity phosphorylation Thr200 LPLLVQRtIARTIVL 452646 7774578 YES lperfetto The tgf-beta type ii receptor (t beta r-ii) is a transmembrane serine/threonine kinase that, upon ligand binding, recruits and phosphorylates a second transmembrane kinase, t beta r-i, as a requirement for signal transduction. In contrast to the relatively innocuous nature of single site mutations in the ttsgsgsg sequence, mutation of thr200 or 204 to valine causes marked losses in ligand-induced phosphorylation and signaling. SIGNOR-32744 SIGNOR-OsteoTGFB Osteoblast: TGF beta TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity phosphorylation Thr204 VQRTIARtIVLQESI 452646 7774578 YES lperfetto The TGF-beta type II receptor (T beta R-II) is a transmembrane serine/threonine kinase that, upon ligand binding, recruits and phosphorylates a second transmembrane kinase, T beta R-I, as a requirement for signal transduction. In contrast to the relatively innocuous nature of single site mutations in the ttsgsgsg sequence, mutation of thr200 or 204 to valine causes marked losses in ligand-induced phosphorylation and signaling. SIGNOR-32748 SIGNOR-OsteoTGFB Osteoblast: TGF beta TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity phosphorylation Thr176 PFISEGTtLKDLIYD -1 8576253 YES giulio giuliani From our present data, it is not easy to deduce the mechanistic significance of serine 172 and threonine 176 of TŒ≤R-I in TGF-Œ≤ signaling. Although it was reported that TGF-Œ≤-induced phosphorylation of these residues was not detected in vivo(22), it is still possible that TŒ≤R-II may phosphorylate these residues as minor phosphorylation site(s). SIGNOR-255961 SIGNOR-OsteoTGFB Osteoblast: TGF beta TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity phosphorylation Thr200 LPLLVQRtIARTIVL -1 8576253 YES giulio giuliani From our present data, it is not easy to deduce the mechanistic significance of serine 172 and threonine 176 of TŒ≤R-I in TGF-Œ≤ signaling. Although it was reported that TGF-Œ≤-induced phosphorylation of these residues was not detected in vivo(22), it is still possible that TŒ≤R-II may phosphorylate these residues as minor phosphorylation site(s). SIGNOR-255962 SIGNOR-OsteoTGFB Osteoblast: TGF beta SMAD3 protein P84022 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates activity binding 9606 BTO:0000007 11331591 YES lperfetto Tgf-beta inhibited the expression of the cbfa1 and osteocalcin genes, whose expression is controlled by cbfa1 in osteoblast-like cell lines. This inhibition was mediated by smad3, which interacts physically with cbfa1 and represses its transcriptional activity at the cbfa1-binding ose2 promoter sequence. SIGNOR-235902 SIGNOR-OsteoTGFB Osteoblast: TGF beta DLX5 protein P56178 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22298955 NO gcesareni Dlx5 can drive runx2 expression and osteogenic differentiation in developing cranial suture mesenchyme , indicat-ing that dlx5 can work as an upstream gene of runx2. SIGNOR-195576 SIGNOR-OsteoTGFB Osteoblast: TGF beta DLX5 protein P56178 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17335796 NO gcesareni Dlx5 can drive runx2 expression and osteogenic differentiation in developing cranial suture mesenchyme. SIGNOR-153454 SIGNOR-OsteoTGFB Osteoblast: TGF beta DLX5 protein P56178 UNIPROT Osteoblast_differentiation phenotype SIGNOR-PH9 SIGNOR up-regulates 10090 12000792 NO Giulio Giuliani In conclusion, Dlx5 and Dlx6 are dynamic regulators of mammalian development, which are absolutely required for proper craniofacial and skeletal development and which display overlapping genetic functions in all tissues in which they are expressed. In addition, they appear to act as essential regulators of chondrogenesis and osteogenesis. SIGNOR-255450 SIGNOR-OsteoTGFB Osteoblast: TGF beta MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9534 7839144 YES lperfetto Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. SIGNOR-232156 SIGNOR-OsteoTGFB Osteoblast: TGF beta MAP3K7 protein O43318 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 11460167 YES lperfetto The activity of tak1 to phosphorylate mkk6, which activates the jnk-p38 kinase pathway, is directly regulated by k63-linked polyubiquitination SIGNOR-109497 SIGNOR-OsteoTGFB Osteoblast: TGF beta MAP3K7 protein O43318 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000222 21902831 YES lperfetto TAK1 can phosphorylate and activate MAP kinase kinase 3/6 (MKK3/6), and numerous studies have demonstrated a requirement for MKK3/6 activity in the initiation of myoblast differentiation, again in a p38-dependent manner. SIGNOR-236093 SIGNOR-OsteoTGFB Osteoblast: TGF beta TGFBR1 protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser423 SPSIRCSsVS 10090 BTO:0005493;BTO:0000165 19458083 YES lperfetto A major event leading to smad3 activation is the tgf-beta-induced, tbetari-mediated phosphorylation at two c-terminal serine residues, ser-423 and ser-425, which triggers dissociation of smad3 from its receptors to form a complex with smad4 and accumulate in the nucleus SIGNOR-235385 SIGNOR-OsteoTGFB Osteoblast: TGF beta TGFBR1 protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser425 SIRCSSVs 10090 BTO:0005493;BTO:0000165 19458083 YES lperfetto A major event leading to Smad3 activation is the TGF-beta-induced, TbetaRI-mediated phosphorylation at two C-terminal serine residues, Ser-423 and Ser-425, which triggers dissociation of Smad3 from its receptors to form a complex with Smad4 and accumulate in the nucleus SIGNOR-235380 SIGNOR-OsteoTGFB Osteoblast: TGF beta TGFBR1 protein P36897 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0002181 18758450 YES lperfetto Here we report that the ubiquitin ligase (e3) traf6 interacts with a consensus motif present in tbetari. The tbetari-traf6 interaction is required for tgf-beta-induced autoubiquitylation of traf6 and subsequent activation of the tak1-p38/jnk pathway, which leads to apoptosis. SIGNOR-236119 SIGNOR-OsteoTGFB Osteoblast: TGF beta TGFBR1 protein P36897 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0000007 18922473 YES gcesareni We report here that TRAF6 is specifically required for the Smad-independent activation of JNK and p38 and its carboxyl TRAF homology domain physically interacts with TGF-² receptors SIGNOR-241918 SIGNOR-OsteoTGFB Osteoblast: TGF beta MAPK14 protein Q16539 UNIPROT DLX5 protein P56178 UNIPROT up-regulates activity phosphorylation Ser34 MHHPSQEsPTLPESS 10090 18056716 YES ggiuliani We show that Dlx5 is a novel substrate for p38 MAPK in vitro and in vivo and that Ser-34 and Ser-217 are the sites phosphorylated by p38 SIGNOR-255792 SIGNOR-OsteoTGFB Osteoblast: TGF beta MAPK14 protein Q16539 UNIPROT SP7 protein Q8TDD2 UNIPROT up-regulates activity phosphorylation 10090 20682789 YES ggiuliani We therefore propose that Osterix binds to Sp1 sequences on target gene promoters and that its phosphorylation by p38 enhances recruitment of coactivators to form transcriptionally active complexes SIGNOR-255791 SIGNOR-OsteoTGFB Osteoblast: TGF beta MAPK14 protein Q16539 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates activity phosphorylation 10090 20551513 YES ggiuliani Mechanistic analysis revealed that the TAK1–MKK3/6–p38 MAPK axis phosphorylated Runx2, promoting its association with the coactivator CREB-binding protein (CBP), which was required to regulate osteoblast genetic programs. These findings reveal an in vivo function for p38β and establish that MAPK signaling is essential for bone formation in vivo. SIGNOR-255777 SIGNOR-OsteoTGFB Osteoblast: TGF beta MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 20551513 YES ggiuliani Expression of a constitutively active mutant of MKK6 (MKK6-glu) (39), but not a kinase-inactive mutant of MKK6 (MKK6-K82A) (39), strongly promoted human MSC differentiation to osteoblasts as shown by increased ALP activity and extracellular matrix mineralization (Figure 4E). Furthermore, MKK6-glu‚Äìexpressing osteoblasts were treated with inhibitors of p38, JNK, and MEK (Figure 4F). Only treatment with the p38 inhibitor SB203580 blocked the effects of MKK6-glu. SIGNOR-255780 SIGNOR-OsteoTGFB Osteoblast: TGF beta MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Thr180 RHTDDEMtGYVATRW 9534 8622669 YES lperfetto These data indicate that mkk6 phosphorylates p38 map kinase on thr-180 and tyr-182, the sites of phosphorylation that activate p38 map kinase SIGNOR-40423 SIGNOR-OsteoTGFB Osteoblast: TGF beta MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr182 TDDEMTGyVATRWYR 9534 8622669 YES lperfetto These data indicate that mkk6 phosphorylates p38 map kinase on thr-180 and tyr-182, the sites of phosphorylation that activate p38 map kinase SIGNOR-40427 SIGNOR-OsteoTGFB Osteoblast: TGF beta MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 10480932 YES lperfetto We have found that p38 mitogen-activated protein kinase, and its direct activator MKK6 are rapidly activated in response to TGF-beta. SIGNOR-70607 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis NfKb-p65/p50 complex SIGNOR-C13 SIGNOR HES1 protein Q14469 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0001938 24300895 NO These data indicate that basal NFκB activity at the conserved +26/+34 site of the HES1 gene promotes its expression, and that glucocorticoids can silence HES1 by inhibiting this activity. SIGNOR-253063 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis PI3K complex SIGNOR-C156 SIGNOR PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 12040186 YES lperfetto The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. SIGNOR-252713 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis PI3K complex SIGNOR-C156 SIGNOR PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates quantity 9606 21798082 YES lperfetto Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate. (pip2). SIGNOR-252722 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis PI3K complex SIGNOR-C156 SIGNOR PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 YES lperfetto Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478 SIGNOR-252712 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 BTO:0000150 19573809 NO lperfetto However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth SIGNOR-252703 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 12167717 NO lperfetto PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473, SIGNOR-252715 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKACA protein P17612 UNIPROT up-regulates chemical activation 9606 16293724 YES gcesareni Pge2 receptors are coupled to the G protein Gs, which causes accumulation of cyclic adenosine monophosphate (cAMP) and activates protein kinase a (PKA), we confirmed that PGE2 treatment or transfection of cells with the active catalytic subunit of PKA also stimulated the activity of a cAMP-responsive-element driven reporter gene (CRE-luc). SIGNOR-141786 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKACA protein P17612 UNIPROT up-regulates chemical activation 9606 BTO:0000007 22863277 YES milica The cAMP signaling cascade can activate protein kinase a (PKA) SIGNOR-198492 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis rosiglitazone chemical CHEBI:50122 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation 9534 7768881 YES An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma) SIGNOR-251646 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis budesonide chemical CHEBI:3207 ChEBI NR3C1 protein P04150 UNIPROT up-regulates activity chemical activation -1 9793625 YES Mometasone furoate (MF, CAS 83919-23-7, Sch 32088), budesonide (BUD, CAS 51372-29-3), fluticasone propionate (FP, CAS 80474-14-2), and triamcinolone acetonide (TA, CAS-76-25-5) are corticosteroids. All of the test compounds had a higher affinity for the recombinant glucocorticoid receptor than the reference glucocorticoid receptor ligand, dexamethasone (DEX, CAS 50-02-2). All compounds showed greater potency than dexamethasone in stimulating transcription of a synthetic target gene regulated by a glucocorticoid response element. SIGNOR-253053 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR GATA2 protein P23769 UNIPROT down-regulates activity phosphorylation Ser401 QTRNRKMsNKSKKSK 9606 BTO:0000876 15837948 YES PI-3K/Akt-dependent manner. lperfetto We show that insulin induces gata2 phosphorylation on serine 401 in a pi-3k/akt-dependent manner. Insulin-dependent phosphorylation of serine 401 impairs gata2 translocation to the nucleus and its dna binding activity SIGNOR-244271 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXA2 protein Q9Y261 UNIPROT down-regulates activity phosphorylation Thr156 KTYRRSYtHAKPPYS 9606 14500912 YES Foxa-2 physically interacts with Akt, a key mediator of the phosphatidylinositol 3-kinase pathway and is phosphorylated at a single conserved site (T156) that is absent in Foxa-1 and Foxa-3 proteins. This Akt phosphorylation site in Foxa-2 is highly conserved from mammals to insects. Mutant Foxa-2T156A is resistant to Akt-mediated phosphorylation, nuclear exclusion, and transcriptional inactivation of Foxa-2-regulated gene expression. SIGNOR-254974 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 21798082 YES lperfetto Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b). SIGNOR-252352 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 10090 BTO:0002572 18423396 YES lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation SIGNOR-252350 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates relocalization 10090 BTO:0002572 18423396 YES lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation SIGNOR-252351 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 YES lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. These results indicate that phosphorylation by PKB/Akt negatively regulates FKHR1 by promoting export from the nucleus. SIGNOR-252346 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 YES lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-252347 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 21440011 YES lperfetto Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs SIGNOR-252348 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser319 TFRPRTSsNASTISG 9606 11237865 YES lperfetto The transcription factor, forkhead in rhabdomyosarcoma (fkhr), is phosphorylated at three amino acid residues (thr-24, ser-256 and ser-319) by protein kinase b (pkb)alpha.Fkhr (forkhead in rhabdomyosarcoma), afx (all1 fused gene from chromosome x) and fkhrl1 (fkhr-like 1) are phosphorylated directly by pkb in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus SIGNOR-252349 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 ChEBI PDE1B protein Q01064 UNIPROT down-regulates activity chemical inhibition 9606 22014080 YES Until now, very few inhibitors of PDE1 were available for evaluating the contribution of PDE1 in tissue and cell function. Vinpocetine (Ahn et al., 1989) and 8-methoxymethyl-IBMX (Ahn et al., 1997) are common PDE1 inhibitors. SIGNOR-253400 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 ChEBI PDE1C protein Q14123 UNIPROT down-regulates activity chemical inhibition 9606 22014080 YES Until now, very few inhibitors of PDE1 were available for evaluating the contribution of PDE1 in tissue and cell function. Vinpocetine (Ahn et al., 1989) and 8-methoxymethyl-IBMX (Ahn et al., 1997) are common PDE1 inhibitors. SIGNOR-253017 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9534 9637919 YES lperfetto In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation. SIGNOR-58313 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 YES lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation -1 9094314 YES gcesareni We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1) SIGNOR-243274 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis PIP3 smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity relocalization 9606 BTO:0001130 23633519 YES lperfetto Akt is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates pips) with phosphate groups at positions 3,4 and 3,4,5 on the inositol ring. SIGNOR-236490 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis PIP3 smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity relocalization 9606 23119004 YES lperfetto Binding of IGF to IGF-1R activates PI3K to generate PIP3 which in turn recruits and activates proteins that contain a pleckstrin homology ph) domain, including AKT and PDK1. SIGNOR-236509 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis PDE1A protein P54750 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI down-regulates quantity chemical modification 9606 22014080 YES PDE1A and PDE1B preferentially hydrolyse cGMP, whereas PDE1C hydrolyses cAMP and cGMP with similar Km values SIGNOR-253398 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis PDE1C protein Q14123 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI down-regulates quantity chemical modification 9606 22014080 YES PDE1A and PDE1B preferentially hydrolyse cGMP, whereas PDE1C hydrolyses cAMP and cGMP with similar Km values SIGNOR-253399 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser393 MQVSSSSsSHSLSAS 9606 10455013 YES lperfetto 3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity SIGNOR-235782 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser396 SSSSSSHsLSASDTG 9606 10455013 YES lperfetto 3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity SIGNOR-236764 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser410 GLPQRSGsNIEQYIH 9606 10455013 YES lperfetto 3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity SIGNOR-236772 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser25 VVLCSCPsPSMVRTQ 9606 10455013 YES lperfetto 3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity SIGNOR-236777 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates activity phosphorylation Ser241 SKQARANsFVGTAQY 9606 11481331 YES miannu In terms of the modulation of PDK1 activity by reversible phosphorylation, five pS sites have been identified on PDK1 in vivo, but only one of these sites, Ser-241 in the activation loop of PDK1, is essential for activity. It seems likely that PDK1 autophosphorylates itself on this residue. SIGNOR-250268 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates activity phosphorylation Ser241 SKQARANsFVGTAQY 9606 10455013 YES lperfetto Pdk1 is itself phosphorylated in vivo and whether phosphorylation plays a role in regulating its activity/ phosphorylation of ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1 SIGNOR-236789 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT down-regulates quantity by destabilization phosphorylation Ser241 SKQARANsFVGTAQY -1 12177059 YES miannu PDK1 kinase activity is negatively regulated by binding to 14-3-3 through the PDK1 autophosphorylation site Ser-241. PDK1 binds to 14-3-3 in vivo and in vitro through the residues surrounding the autophosphorylation site Ser-241 and that the association is achieved only when Ser-241 has been phosphorylated SIGNOR-250077 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10090 12808134 YES lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1). SIGNOR-134477 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15743829 YES lperfetto 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt), SIGNOR-244469 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10116 BTO:0000142 10226025 YES lperfetto Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown. SIGNOR-244421 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 YES lperfetto The activation of PKBbeta and PKBamma by PDK11 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma) SIGNOR-244480 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr992 DGPLGPLyASSNPEY -1 3166375 YES lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-106522 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr999 YASSNPEyLSASDVF -1 3166375 YES lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-106526 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1355 SLGFKRSyEEHIPYT -1 3166375 YES lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-22577 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1361 SYEEHIPyTHMNGGK -1 3166375 YES lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-233560 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1011 DVFPCSVyVPDEWEV -1 3166375 YES lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-233564 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1185 FGMTRDIyETDYYRK -1 2449432 YES lperfetto We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151; SIGNOR-106510 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1189 RDIYETDyYRKGGKG -1 2449432 YES lperfetto We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151; SIGNOR-106514 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1190 DIYETDYyRKGGKGL -1 2449432 YES lperfetto We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151; SIGNOR-106518 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis INSR protein P06213 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation Tyr580 LRKTRDQyLMWLTQK 9534 BTO:0000298 8385099 YES The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor. SIGNOR-252691 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis INSR protein P06213 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation Tyr368 STKMHGDyTLTLRKG 9534 8385099 YES The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor. SIGNOR-252692 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis INSR protein P06213 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation Tyr607 NENTEDQySLVEDDE 9534 BTO:0000298 8385099 YES The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor. SIGNOR-252693 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis FOXO1 protein Q12778 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 16670091 NO lperfetto FOXO1 coexpression dose-dependently repressed transcription from either the PPARgamma 1 or PPARgamma2 promoter reporter by 65%, whereas insulin (100 nm, 20-24 h) either partially or completely reversed this effect. SIGNOR-218013 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis FOXO1 protein Q12778 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 18423396 NO fspada Akt1/Pkb-alpha was found to be the major regulator of phosphorylation and nuclear export of Foxo1, whose presence in the nucleus strongly attenuates adipocyte differentiation. SIGNOR-178281 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis FOXO1 protein Q12778 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 12530968 NO Constitutively active Foxo1 prevents the differentiation of preadipocytes, while dominant-negative Foxo1 restores adipocyte differentiation of fibroblasts from insulin receptor-deficient mice. SIGNOR-254973 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis INS protein P01308 UNIPROT INSR protein P06213 UNIPROT up-regulates activity binding 10029 16956584 YES lperfetto Insulin binds to the alpha subunit of the insulin receptor (IR) on the cell surface. SIGNOR-236748 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis INS protein P01308 UNIPROT INSR protein P06213 UNIPROT up-regulates activity binding 9606 2550426 YES lperfetto Our previous studies indicated that amino acid residues 240-250 in the cysteine-rich region of the human insulin receptor alpha-subunit constitute a site in which insulin binds. SIGNOR-23001 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis FOXA2 protein Q9Y261 UNIPROT DLK1 protein P80370 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 12865419 YES Taken together, these data suggest that Foxa-2 is a direct transcriptional activator of the Pref-1 gene. SIGNOR-254971 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis DLK1 protein P80370 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 8500166 NO This indicates that pref-1 functions as a negative regulator of adipocyte differentiation, possibly in a manner analogous to EGF-like proteins that govern cell fate decisions in invertebrates. SIGNOR-254980 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis CREB1 protein P16220 UNIPROT CEBPB protein P17676 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 14593102 NO lperfetto Expression of constitutively active CREB strongly activated C/EBPbeta promoter-reporter genes, induced expression of endogenous C/EBPbeta, and caused adipogenesis in the absence of the hormonal inducers normally required SIGNOR-250573 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis CREB1 protein P16220 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000759 14614508 NO HES-1 is a direct CREB target in vivo. SIGNOR-254742 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis HES1 protein Q14469 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates activity 9606 BTO:0001938 24300895 YES Altering the expression of HES1 did not obviously affect GR abundance (Figure 3A). However, genome-wide microarrays revealed that overexpression of HES1 resulted in inhibition of GR-mediated changes in the glucocorticoid regulated transcriptome, as compared to non-overexpressing controls SIGNOR-253064 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis HES1 protein Q14469 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 14614508 NO Overexpression of HES-1 fully repressed PPAR-g even in the presence of the ACREB inhibitor, showing that HES-1 acts downstream of CREB SIGNOR-254743 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis HES1 protein Q14469 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 BTO:0000011 16282371 NO Notch signaling blocks differentiation of 3T3-L1 preadipocytes, and this can be mimicked by constitutive expression of the Notch target gene Hes-1 SIGNOR-253058 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis PRKACA protein P17612 UNIPROT PPARG protein P37231 UNIPROT up-regulates activity 10090 BTO:0000011 20638365 NO Here we showed that cAMP-induced activation of protein kinase A (PKA) and Akt is essential for the transcriptional activation of PPAR-gamma SIGNOR-253019 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001103 21902831 YES gcesareni Phosphorylation of CREB by PKA allows it to initiate the transcription of genes that contain a CRE element, two of which are PAX3 and MYF5. SIGNOR-176560 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000669 15568017 YES gcesareni Using a combination of in vitro explant assays, mutant analysis and gene delivery into mouse embryos cultured ex vivo, we demonstrate that adenylyl cyclase signalling via PKA and its target transcription factor CREB are required for WNT-directed myogenic gene expression. SIGNOR-131307 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis GATA2 protein P23769 UNIPROT PPARG protein P37231 UNIPROT down-regulates activity 9606 20510530 YES fferrentino GATA2 interacts directly with PPARG and C/EBP a , which may deplete PPARG involved in the promotion of adipogenesis SIGNOR-132949 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis GATA2 protein P23769 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 11021798 NO fspada Constitutive gata-2 and gata-3 expression suppressed adipocyte differentiation and trapped cells at the preadipocyte stage. SIGNOR-78659 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis CEBPB protein P17676 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity transcriptional regulation 10090 16431920 YES fspada These data suggest that c/CEBP beta activates a single unified pathway of adipogenesis involving its stimulation of PPARgamma expression, which then activates C/EBP alpha expression by dislodging HDAC1 from the promoter for degradation in the proteasome SIGNOR-143952 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis ADCY1 protein Q08828 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates chemical modification 9606 22863277 YES milica To further explore the role of camp signaling in the hippo pathway, we treated cells with forskolin, an activator of adenylyl cyclase that results in cAMP production. SIGNOR-198486 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis ADCY1 protein Q08828 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates chemical modification 9606 17251915 YES gcesareni Typically Gas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate many molecules, including phospholipases, ion channels and lipid kinases. SIGNOR-152546 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis NR3C1 protein P04150 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates binding 10116 18762022 YES The GR directly interferes with Hes1 promoter activity, triggering the recruitment of histone deacetylase (HDAC) activities to the Hes1 gene SIGNOR-253057 SIGNOR-PIVIOA Pericyte: In vitro induction of adipogenesis HDAC1 protein Q13547 UNIPROT HES1 protein Q14469 UNIPROT down-regulates quantity transcriptional regulation 10090 18762022 NO These data suggest that the GR recruits cellular HDAC activities to the Hes1 promoter, thereby conferring transcriptional repression in response to GC signaling. SIGNOR-253054 SIGNOR-PMTC Pericyte: Myogenic transcriptional cascade PAX7 protein P23759 UNIPROT MYF5 protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 18066051 YES Simone Vumbaca Together, these experiments indicate that Pax7 enforces satellite cell commitment by recruiting a HMT complex to Myf5, resulting in transcriptional activation. SIGNOR-255641 SIGNOR-PMTC Pericyte: Myogenic transcriptional cascade PAX7 protein P23759 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates quantity by destabilization 10090 17548510 NO Simone Vumbaca Previously, we showed that Pax7 overexpression in adult primary myoblasts down-regulates MyoD and prevents myogenin induction, inhibiting myogenesis. We show that Pax7 prevents muscle differentiation independently of its transcriptional activity, affecting MyoD function. [...] Pax7 expression affects MyoD protein stability SIGNOR-255637 SIGNOR-PMTC Pericyte: Myogenic transcriptional cascade MYOG protein P15173 UNIPROT MYF6 protein P23409 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001103 7739551 YES Simone Vumbaca [...] confirming that myogenin binds to the E1 and E2 E boxes located in close proximity to the MRF4 transcription start site. SIGNOR-255642 SIGNOR-PMTC Pericyte: Myogenic transcriptional cascade MYOG protein P15173 UNIPROT PAX7 protein P23759 UNIPROT down-regulates quantity by destabilization 10090 BTO:0004058 17548510 NO Simone Vumbaca Indeed, we observed a reduction in Pax7 protein levels upon ectopic myogenin expression in MM14 myoblasts, even under proliferation conditions SIGNOR-255638 SIGNOR-PMTC Pericyte: Myogenic transcriptional cascade MYOG protein P15173 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates activity BTO:0001103 7532173 NO Simone Vumbaca These results suggest that at least initially, the muscle-forming regions contained cells with myogenic potential, and that this potential is lost in the myogenin mutants as development proceeds. SIGNOR-255644 SIGNOR-PMTC Pericyte: Myogenic transcriptional cascade MYF6 protein P23409 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates activity BTO:0001103 7532173 NO Simone Vumbaca Finally, MRF4 may be responsible for the final myogenic events of the fully differentiated myofiber SIGNOR-255645 SIGNOR-PMTC Pericyte: Myogenic transcriptional cascade MYF6 protein P23409 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 NO miannu The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop--helix (bhlh) motif that mediates dimerization and dna binding. / myogenic bhlh proteins form heterodimers with ubiquitous bhlh proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. SIGNOR-37455 SIGNOR-PMTC Pericyte: Myogenic transcriptional cascade MEF2D protein Q14814 UNIPROT MYF6 protein P23409 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165;BTO:0000222 7739551 YES lperfetto Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis. SIGNOR-238715 SIGNOR-PMTC Pericyte: Myogenic transcriptional cascade MEF2C protein Q06413 UNIPROT MYF6 protein P23409 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165;BTO:0000222 7739551 YES lperfetto Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis. SIGNOR-238652 SIGNOR-PMTC Pericyte: Myogenic transcriptional cascade MYOD1 protein P15172 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001103 15870273 YES Simone Vumbaca We suggest that the interaction between MyoD and Pbx is necessary to initially target MyoD to the myogenin promoter SIGNOR-255639 SIGNOR-PMTC Pericyte: Myogenic transcriptional cascade MYOD1 protein P15172 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001103 12694204 YES Simone Vumbaca We conclude that MyoD is the major MRF that binds to the E-box from the myogenin promoter during differentiation. SIGNOR-255640 SIGNOR-PMTC Pericyte: Myogenic transcriptional cascade MYOD1 protein P15172 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0001103 16275751 NO andrea cerquone perpetuini Together, these results support the notion that Myf5 functions toward myoblast proliferation, whereas MyoD prepares myoblasts for efficient differentiation. SIGNOR-255417 SIGNOR-PMTC Pericyte: Myogenic transcriptional cascade MYF5 protein P13349 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates activity BTO:0001103 17495111 NO Simone Vumbaca In summary, the absence of Myf5 clearly reduced the initial expansion of satellite cell-derived transient amplifying cells and resulted in a shift of the ratio of satellite cell subpopulations but did not affect the specification and generation of specific subpopulations of satellite cell-derived cells such as reserve cells, amplifying cells, and differentiating mature myogenic cells. SIGNOR-255643 SIGNOR-PMTC Pericyte: Myogenic transcriptional cascade MEF2A protein Q02078 UNIPROT MYF6 protein P23409 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 7739551 YES lperfetto Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis. SIGNOR-238709 SIGNOR-PPAMG Pericyte: Prostaglandins and myogenesis celecoxib chemical CHEBI:41423 ChEBI PTGS2 protein P35354 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni SIGNOR-190928 SIGNOR-PPAMG Pericyte: Prostaglandins and myogenesis Pravadoline chemical CID:56463 ChEBI PTGS2 protein P35354 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni SIGNOR-206322 SIGNOR-PPAMG Pericyte: Prostaglandins and myogenesis acetylsalicylic acid chemical CHEBI:15365 ChEBI PTGS2 protein P35354 UNIPROT down-regulates chemical inhibition 9606 11809688 YES gcesareni Nsaids inhibit cyclooxygenase (cox) isozymes, which are responsible for the committed step in prostaglandin biosynthesis, and this has been considered the primary mechanism by which nsaids exert their antitumorigenic effects. SIGNOR-114380 SIGNOR-PPAMG Pericyte: Prostaglandins and myogenesis arachidonic acid smallmolecule CHEBI:15843 ChEBI PTGS2 protein P35354 UNIPROT up-regulates 9606 15878913 NO miannu AA increases PC-3 prostate tumor cell growth, total DNA content and endogenous PGE 2 levels via induction of c-fos , cPLA 2 and cox-2 mRNA transcription. SIGNOR-255394 SIGNOR-PPAMG Pericyte: Prostaglandins and myogenesis prostaglandin F2alpha smallmolecule CHEBI:15553 ChEBI Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 9606 20219869 NO apalma Prostaglandins are able to affect muscle cell proliferation (142), differentiation (96) and fusion (141), and can also modulate muscle fiber growth and the synthesis and degradation of proteins in muscle SIGNOR-256213 SIGNOR-PPAMG Pericyte: Prostaglandins and myogenesis prostaglandin F2alpha smallmolecule CHEBI:15553 ChEBI Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 20219869 NO apalma Prostaglandins are able to affect muscle cell proliferation (142), differentiation (96) and fusion (141), and can also modulate muscle fiber growth and the synthesis and degradation of proteins in muscle SIGNOR-255360 SIGNOR-PPAMG Pericyte: Prostaglandins and myogenesis prostaglandin F2alpha smallmolecule CHEBI:15553 ChEBI Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 3308494 NO apalma The results suggest a role for prostanoids in the regulation of both human myoblast proliferation and differentiation SIGNOR-255362 SIGNOR-PPAMG Pericyte: Prostaglandins and myogenesis PTGS2 protein P35354 UNIPROT IL4 protein P05112 UNIPROT up-regulates 9606 22225874 YES FFerrentino Cox2 Is a Direct Srf Target Gene and Controls Il4 Expression SIGNOR-255967 SIGNOR-PPAMG Pericyte: Prostaglandins and myogenesis PTGS2 protein P35354 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0001103 20219869 YES apalma Furthermore, COX-2 inhibition reduced MyoD expression in regenerating muscle, suggesting a role for COX-2 in modulating muscle differentiation, as well as growth SIGNOR-256214 SIGNOR-PPAMG Pericyte: Prostaglandins and myogenesis PTGS2 protein P35354 UNIPROT prostaglandin F2alpha smallmolecule CHEBI:15553 ChEBI up-regulates chemical modification 9606 11751058 YES gcesareni Cox catalyzes two enzymatic activities;namely, the conversion of aa to the hydroperoxy endoperoxide pgg2, followed by its subsequent reduction to the labile product pgh2. Pgh2_ is the common substrate for a number of different cell-specific synthases, which convert pgh2_ to the individual pgs or tx, including pge2, pgi2_ (prostacyclin), pgd2, pgf2alfa, and txa2. SIGNOR-113291 SIGNOR-PPAMG Pericyte: Prostaglandins and myogenesis SRF protein P11831 UNIPROT IL6 protein P05231 UNIPROT up-regulates 9606 22225874 YES FFerrentino Srf within myofibers modulates Il6 and Cox2/Il4 expressions and, therefore, exerts a paracrine control of satellite cell proliferation and fusion, respectively, which in turn support skeletal muscle hypertrophy. SIGNOR-255966 SIGNOR-PPAMG Pericyte: Prostaglandins and myogenesis SRF protein P11831 UNIPROT PTGS2 protein P35354 UNIPROT up-regulates 9606 22225874 YES FFerrentino Srf within myofibers modulates Il6 and Cox2/Il4 expressions and, therefore, exerts a paracrine control of satellite cell proliferation and fusion, respectively, which in turn support skeletal muscle hypertrophy. SIGNOR-255965 SIGNOR-PPAMG Pericyte: Prostaglandins and myogenesis MYOD1 protein P15172 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 NO lperfetto The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop-helix (bHLH) motif that mediates dimerization and dna binding. [...] myogenic bHLH proteins form heterodimers with ubiquitous bHLH proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. SIGNOR-37458 SIGNOR-PPAMG Pericyte: Prostaglandins and myogenesis IL4 protein P05112 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 10090 12757709 NO miannu These data demonstrate that following myotube formation, myotubes recruit myoblast fusion by secretion of IL-4, leading to muscle growth SIGNOR-255896 SIGNOR-ScCA Satellite: Calcium&myogenesis Calcineurin complex SIGNOR-C155 SIGNOR NFATC1 protein O95644 UNIPROT up-regulates dephosphorylation 9606 21880741 YES gcesareni Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. SIGNOR-252323 SIGNOR-ScCA Satellite: Calcium&myogenesis Calcineurin complex SIGNOR-C155 SIGNOR NFATC1 protein O95644 UNIPROT up-regulates dephosphorylation 9606 BTO:0000782 14722106 YES gcesareni Once activated, calcineurin directly dephosphorylates NFAT proteins that are present in a hyperphosphorylated latent form in the cytoplasm and induces their rapid translocation into the nucleus, where in concert with nuclear partner proteins such as the AP-1 transcription factor complex, they are able to bind cooperatively to their target promoter elements and activate the transcription of specific NFAT target genes SIGNOR-252313 SIGNOR-ScCA Satellite: Calcium&myogenesis Calcineurin complex SIGNOR-C155 SIGNOR MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0001103 15829723 NO apalma Calcineurin can activate the transcription factors myocyte enhancer factor-2 and MyoD, which leads to the subsequent induction of myogenin and muscle differentiation (22). In addition, inhibition of calcineurin prevents the initiation of early stages of muscle differentiation SIGNOR-255103 SIGNOR-ScCA Satellite: Calcium&myogenesis Calcineurin complex SIGNOR-C155 SIGNOR MEF2C protein Q06413 UNIPROT up-regulates 9606 BTO:0001103 11062529 NO gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. SIGNOR-252309 SIGNOR-ScCA Satellite: Calcium&myogenesis cyclosporin A chemical CHEBI:4031 ChEBI Calcineurin complex SIGNOR-C155 SIGNOR down-regulates chemical inhibition 9606 15276472 YES gcesareni Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins. SIGNOR-252307 SIGNOR-ScCA Satellite: Calcium&myogenesis cyclosporin A chemical CHEBI:4031 ChEBI Calcineurin complex SIGNOR-C155 SIGNOR down-regulates chemical inhibition 10116 BTO:0001103 15829723 YES apalma On one hand, inhibition of calcineurin with cyclosporin A (CsA) significantly reduced the growth of both the slow/type I soleus muscle and fast/type II plantaris muscle in normal, ambulatory rats SIGNOR-255102 SIGNOR-ScCA Satellite: Calcium&myogenesis calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM1 protein P0DP23 UNIPROT up-regulates chemical activation 9606 10884684 YES lperfetto Calmodulin is the best studied and prototypical example of the e-f-hand family of ca2+-sensing proteins. In the event of a transient rise in Ca2+, the Ca2+ ion is coordinated in each Ca2+-binding loop of Ca2+–CaM by seven, primarily carboxylate, ligands. The binding of Ca2+ leads to substantial alterations in the interhelical angles within the E–F hands in each domain and dramatically changes the two domains of CaM to produce more ‘openÂ’ conformations SIGNOR-78915 SIGNOR-ScCA Satellite: Calcium&myogenesis calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM1 protein P0DP23 UNIPROT up-regulates chemical activation 10090 10448861 YES lperfetto Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1. SIGNOR-235590 SIGNOR-ScCA Satellite: Calcium&myogenesis CALM1 protein P0DP23 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR up-regulates binding 9606 11796223 YES gcesareni Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. SIGNOR-252337 SIGNOR-ScCA Satellite: Calcium&myogenesis MYOG protein P15173 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0001103 28163303 NO apalma During early stages of myogenesis, CIITA binds directly to myogenin (MYOG) and inactivates it, preventing MYOG-mediated induction of myogenic genes that are required for muscle differentiation and function SIGNOR-255112 SIGNOR-ScCA Satellite: Calcium&myogenesis MYOG protein P15173 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates activity BTO:0001103 7532173 NO Simone Vumbaca These results suggest that at least initially, the muscle-forming regions contained cells with myogenic potential, and that this potential is lost in the myogenin mutants as development proceeds. SIGNOR-255644 SIGNOR-ScCA Satellite: Calcium&myogenesis MEF2C protein Q06413 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 9606 9418854 YES lperfetto Myod-e protein heterodimers interact with mef2 proteins to synergistically activate myogenesis. SIGNOR-54089 SIGNOR-ScCA Satellite: Calcium&myogenesis MYOD1 protein P15172 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18676376 NO gcesareni € provide a novel transcriptional paradigm for the first steps of myogenesis, where a calcineurin/NFATc3 pathway regulates myogenin induction in cooperation with MyoD during myogenesis. SIGNOR-235009 SIGNOR-ScCA Satellite: Calcium&myogenesis MYOD1 protein P15172 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001103 12694204 YES Simone Vumbaca We conclude that MyoD is the major MRF that binds to the E-box from the myogenin promoter during differentiation. SIGNOR-255640 SIGNOR-ScCA Satellite: Calcium&myogenesis MYOD1 protein P15172 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 NO lperfetto We observed that the homeodomain factor pbx1, which cooperates with myod to stimulate myogenin expression, is constitutively bound to the myogenin promoter in a swi/snf-independent manner, suggesting a two-step mechanism in which myod initially interacts indirectly with the myogenin promoter and attracts chromatin-remodeling enzymes, which then facilitate direct binding by myod and other regulatory proteins. SIGNOR-135984 SIGNOR-ScCA Satellite: Calcium&myogenesis MYOD1 protein P15172 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 NO lperfetto The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop-helix (bHLH) motif that mediates dimerization and dna binding. [...] myogenic bHLH proteins form heterodimers with ubiquitous bHLH proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. SIGNOR-37458 SIGNOR-ScCA Satellite: Calcium&myogenesis NFATC1 protein O95644 UNIPROT Myotube_hypertrophy phenotype SIGNOR-PH20 SIGNOR up-regulates transcriptional regulation 9606 BTO:0001103 14729474 NO apalma To summarize, these two studies have generated important insights into the control of skeletal muscle hypertrophy by the calcineurin/NFATc1 signaling pathway SIGNOR-256215 SIGNOR-ScCA Satellite: Calcium&myogenesis IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1161 FGMTRDIyETDYYRK 9606 7493944 YES lperfetto Insulin and insulin-like growth factor (igf-i) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor. SIGNOR-26582 SIGNOR-ScCA Satellite: Calcium&myogenesis IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1161 FGMTRDIyETDYYRK -1 8940173 YES miannu The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246248 SIGNOR-ScCA Satellite: Calcium&myogenesis IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1166 DIYETDYyRKGGKGL -1 8940173 YES miannu The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246244 SIGNOR-ScCA Satellite: Calcium&myogenesis IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1166 DIYETDYyRKGGKGL 9606 7493944 YES lperfetto Insulin and insulin-like growth factor (igf-i) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor. SIGNOR-26590 SIGNOR-ScCA Satellite: Calcium&myogenesis IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1346 SFDERQPyAHMNGGR -1 8940173 YES miannu The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246260 SIGNOR-ScCA Satellite: Calcium&myogenesis IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr1165 RDIYETDyYRKGGKG 9606 7493944 YES lperfetto Insulin and insulin-like growth factor (IGF-I) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor. SIGNOR-26586 SIGNOR-ScCA Satellite: Calcium&myogenesis IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr973 RLGNGVLyASVNPEY -1 7493944 YES lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinase. We mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246252 SIGNOR-ScCA Satellite: Calcium&myogenesis IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr980 YASVNPEyFSAADVY -1 7493944 YES lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinase. We mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246256 SIGNOR-ScCA Satellite: Calcium&myogenesis IGF1R protein P08069 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates 9606 15829723 NO apalma Mechanical loading increases IGF-I release, and IGF-I can stimulate Ca2+ influx and thereby activate calcineurin SIGNOR-255100 SIGNOR-ScCA Satellite: Calcium&myogenesis IGF1 protein P05019 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity binding 9606 21798082 YES lperfetto Binding of IGF1 to its receptor leads to activation of its intrinsic tyrosine kinase and autophosphorylation, thus generating docking sites for insulin receptor substrate (IRS), which is also phosphorylated by the IGF1 receptor. SIGNOR-175662 SIGNOR-ScCCR2 Satellite: CCR2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 20219869 NO apalma ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation SIGNOR-256216 SIGNOR-ScCCR2 Satellite: CCR2 CCL2 protein P13500 UNIPROT CCR2 protein P41597 UNIPROT up-regulates activity binding 9606 20219869 YES areggio The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation.  SIGNOR-255113 SIGNOR-ScCCR2 Satellite: CCR2 CCR1 protein P32246 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 20219869 YES areggio The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation. Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. SIGNOR-255118 SIGNOR-ScCCR2 Satellite: CCR2 CCR2 protein P41597 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 20219869 YES areggio The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation. Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. SIGNOR-255117 SIGNOR-ScCCR2 Satellite: CCR2 CCL3 protein P10147 UNIPROT CCR5 protein P51681 UNIPROT up-regulates activity binding 10090 15075201 YES lperfetto The purpose of this study was to determine whether certain chemokines, which are highly expressed in injured skeletal muscle, are involved in the repair and functional recovery of the muscle after traumatic injury. In wild-type control mice, mRNA transcripts of macrophage inflammatory protein (MIP)-1􏰂, MIP-1􏰃, and monocyte chemoattractant protein (MCP)-1 as well as their major receptors, CCR5 and CCR2, increased after freeze injury and gradu- ally returned to control (uninjured) levels by 14 days. SIGNOR-251724 SIGNOR-ScCCR2 Satellite: CCR2 CCL3 protein P10147 UNIPROT CCR5 protein P51681 UNIPROT up-regulates activity binding 10090 20219869 YES areggio The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation.  SIGNOR-255115 SIGNOR-ScCCR2 Satellite: CCR2 CCL3 protein P10147 UNIPROT CCR2 protein P41597 UNIPROT up-regulates activity binding 10090 15075201 YES lperfetto The purpose of this study was to determine whether certain chemokines, which are highly expressed in injured skeletal muscle, are involved in the repair and functional recovery of the muscle after traumatic injury. In wild-type control mice, mRNA transcripts of macrophage inflammatory protein (MIP)-1􏰂, MIP-1􏰃, and monocyte chemoattractant protein (MCP)-1 as well as their major receptors, CCR5 and CCR2, increased after freeze injury and gradu- ally returned to control (uninjured) levels by 14 days. SIGNOR-251723 SIGNOR-ScCCR2 Satellite: CCR2 CCL3 protein P10147 UNIPROT CCR1 protein P32246 UNIPROT up-regulates binding 9606 10734056 YES CCR1 is also activated by MIP-1α, MCP-2, and MCP-3, although maximum responses are only obtained with RANTES and MIP-1α. SIGNOR-254366 SIGNOR-ScCCR2 Satellite: CCR2 CCL3 protein P10147 UNIPROT CCR1 protein P32246 UNIPROT up-regulates activity binding 9606 20219869 YES areggio The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation.  SIGNOR-255114 SIGNOR-ScCCR2 Satellite: CCR2 CCR5 protein P51681 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 20219869 YES areggio The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation. Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. SIGNOR-255119 SIGNOR-ScCCR2 Satellite: CCR2 CCL4 protein P13236 UNIPROT CCR5 protein P51681 UNIPROT up-regulates activity binding 10090 20219869 YES areggio The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation.  SIGNOR-255116 SIGNOR-ScDGC Satellite: Dystrophin glycoprotein complex regulation MAPK12/CARM1 complex SIGNOR-C218 SIGNOR SNTB1 protein Q13884 UNIPROT up-regulates activity binding 29681515 YES apalma Basal localization of the p38γ/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through β1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38γ/β1-syntrophin interactions are abrogated SIGNOR-255978 SIGNOR-ScDGC Satellite: Dystrophin glycoprotein complex regulation PAX7 protein P23759 UNIPROT MYF5 protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 29681515 NO apalma Carm1 specifically methylates Pax7 at multiple arginine residues in the N terminus of Pax7, facilitating the recruitment of the ASH2L:MLL1/2:WDR5:RBBP5 histone H3 lysine 4 (H3K4) methyltransferase complex to the proximal promoter of Myf5 resulting in permissive H3K4 tri-methylation (H3K4me3) of the surrounding chromatin SIGNOR-255899 SIGNOR-ScDGC Satellite: Dystrophin glycoprotein complex regulation PAX7 protein P23759 UNIPROT Quiescence phenotype SIGNOR-PH25 SIGNOR up-regulates BTO:0001103 15501225 NO svumbaca Our work presented here provides a possible mechanism involving Pax-7 that allow satellite cells to exit the cell cycle, down-regulate MyoD, and prevent myogenin induction, phenotypes characteristic of the quiescent satellite cell. SIGNOR-255366 SIGNOR-ScDGC Satellite: Dystrophin glycoprotein complex regulation MAPK12 protein P53778 UNIPROT CARM1 protein Q86X55 UNIPROT down-regulates activity phosphorylation Ser595 GPAISMAsPMSIPTN 10090 29681515 YES apalma Here, we identify a role for the mitogen-activated protein kinase (MAPK) p38g/MAPK12 as a critical regulator of satellite stem cell fate through phosphorylation of Carm1. SIGNOR-255897 SIGNOR-ScDGC Satellite: Dystrophin glycoprotein complex regulation MAPK12 protein P53778 UNIPROT MAPK12/CARM1 complex SIGNOR-C218 SIGNOR form complex binding 29681515 YES apalma Basal localization of the p38γ/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through β1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38γ/β1-syntrophin interactions are abrogated SIGNOR-255981 SIGNOR-ScDGC Satellite: Dystrophin glycoprotein complex regulation SNTB1 protein Q13884 UNIPROT MAPK12 protein P53778 UNIPROT down-regulates binding 10090 BTO:0002314 BTO:0001103 29681515 YES apalma Basal localization of the p38g/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through b1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38g/b1-syntrophin interactions are abrogated, resulting in enhanced Carm1 phosphorylation SIGNOR-255901 SIGNOR-ScDGC Satellite: Dystrophin glycoprotein complex regulation SNTB1 protein Q13884 UNIPROT MAPK12 protein P53778 UNIPROT down-regulates 10090 BTO:0002314 BTO:0001103 29681515 YES apalma [...] suggesting that, during an asymmetric cell division, p38gamma localization would be basally restricted by the DGC complex via its interaction with beta-1-syntrophin. SIGNOR-255903 SIGNOR-ScDGC Satellite: Dystrophin glycoprotein complex regulation SNTB1 protein Q13884 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding BTO:0001103 29681515 YES apalma Basal localization of the p38γ/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through β1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38γ/β1-syntrophin interactions are abrogated SIGNOR-255979 SIGNOR-ScDGC Satellite: Dystrophin glycoprotein complex regulation CARM1 protein Q86X55 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates methylation 10090 BTO:0001103 29163212 YES FFerrentino The first evidence alluding to a role of PRMTs in mediating skeletal muscle plasticity, specifically myogenesis, arose from the identification of CARM1 as a glucocorticoid receptor-interacting protein 1 (GRIP1) binding protein. (Chen et al., 2000). Here, GRIP1 and MEF2 were co-expressed in the nucleus during skeletal muscle differentiation. These initial findings led to an investigation that revealed that this methyltransferase was responsible for coactivating the transcription of myocyte enhancer factor-2C (MEF2C) via GRIP1  SIGNOR-255964 SIGNOR-ScDGC Satellite: Dystrophin glycoprotein complex regulation CARM1 protein Q86X55 UNIPROT PAX7 protein P23759 UNIPROT up-regulates methylation 10090 BTO:0002314 BTO:0001103 29681515 YES apalma Carm1 specifically methylates Pax7 at multiple arginine residues in the N terminus of Pax7 SIGNOR-255898 SIGNOR-ScDGC Satellite: Dystrophin glycoprotein complex regulation CARM1 protein Q86X55 UNIPROT MAPK12/CARM1 complex SIGNOR-C218 SIGNOR form complex binding BTO:0001103 29681515 YES apalma Basal localization of the p38γ/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through β1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38γ/β1-syntrophin interactions are abrogated SIGNOR-255980 SIGNOR-ScDGC Satellite: Dystrophin glycoprotein complex regulation MYOD1 protein P15172 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 NO lperfetto The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop-helix (bHLH) motif that mediates dimerization and dna binding. [...] myogenic bHLH proteins form heterodimers with ubiquitous bHLH proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. SIGNOR-37458 SIGNOR-ScDGC Satellite: Dystrophin glycoprotein complex regulation MYF5 protein P13349 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 NO miannu The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop--helix (bhlh) motif that mediates dimerization and dna binding. / myogenic bhlh proteins form heterodimers with ubiquitous bhlh proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. SIGNOR-37409 SIGNOR-ScDGC Satellite: Dystrophin glycoprotein complex regulation MEF2A protein Q02078 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 9606 BTO:0000887;BTO:0001103 9418854 YES lperfetto Myod-e protein heterodimers interact with mef2 proteins to synergistically activate myogenesis. SIGNOR-54086 SIGNOR-ScFSTTR Satellite: FST transcriptional regulation NFATC2 protein Q13469 UNIPROT FST protein P19883 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15130492 YES lperfetto MyoD, CREB, and NFAT Mediate the Transcriptional Activation of the Follistatin Promoter Induced by TSA SIGNOR-251729 SIGNOR-ScFSTTR Satellite: FST transcriptional regulation SMAD3 protein P84022 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates activity binding 10090 BTO:0000165 11711431 YES azuccotti We show that the TGF-beta intracellular effector Smad3, but not Smad2, mediates the inhibition of myogenic differentiation in MyoD-expressing C3H10T1/2 cells and C2C12 myoblasts by repressing the activity of the MyoD family of transcriptional factors. SIGNOR-252071 SIGNOR-ScFSTTR Satellite: FST transcriptional regulation FST protein P19883 UNIPROT MSTN protein O14793 UNIPROT down-regulates activity binding 10090 24627466 YES lperfetto Follistatin (FST) is a member of the tissue growth factor beta family and is a secreted glycoprotein that antagonizes many members of the family, including activin A, growth differentiation factor 11, and myostatin. FST315-deltaHBS-Fc induced improvements in muscle repair after injury/atrophy by modulating the early inflammatory phase allowing for increased macrophage density, and Pax7-positive cells leading to an accelerated restoration of myofibers and muscle function. SIGNOR-251717 SIGNOR-ScFSTTR Satellite: FST transcriptional regulation LEF1 protein Q9UJU2 UNIPROT MYF5 protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 16936075 NO The other members of the Lef1 HMGB1 protein super-family, Tcf1 and Tcf3, were also expressed in the PSM and the newly formed somites, although at a lower level than was Lef1. gcesareni Furthermore, we show that direct activation is mediated by binding of the tcf-lef/ - catenin complex to the myf5 epaxial enhancer and to a newly identified element upstream of this enhancer. SIGNOR-149170 SIGNOR-ScFSTTR Satellite: FST transcriptional regulation LEF1 protein Q9UJU2 UNIPROT FST protein P19883 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 24344199 YES lperfetto We further demonstrate that Fst is a direct target of the WNT/β-catenin pathway. Activation and inactivation of β-catenin induced and inhibited Fst expression, respectively, in both C2C12 cells and mouse embryos. Specific TCF/LEF1 binding sites within the promoter and intron 1 region of the Fst gene were required for RSPO2 and WNT/β-catenin-induced Fst expression. SIGNOR-251722 SIGNOR-ScFSTTR Satellite: FST transcriptional regulation MSTN protein O14793 UNIPROT ACVR2B protein Q13705 UNIPROT up-regulates activity binding 10090 11459935 YES gcesareni The purified C-terminal myostatin dimer was capable of binding the activin type II receptors, Act RIIB and, to a lesser extent, Act RIIA SIGNOR-235153 SIGNOR-ScFSTTR Satellite: FST transcriptional regulation CREB1 protein P16220 UNIPROT FST protein P19883 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 15130492 NO lperfetto MyoD, CREB, and NFAT Mediate the Transcriptional Activation of the Follistatin Promoter Induced by TSA SIGNOR-251714 SIGNOR-ScFSTTR Satellite: FST transcriptional regulation ACVR2B protein Q13705 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation 10090 21966641 YES areggio It has been suggested that binding of myostatin to the ActRIIB results in the phosphorylation of two serine residues of Smad2 or Smad3 at COOH domains SIGNOR-254985 SIGNOR-ScFSTTR Satellite: FST transcriptional regulation CTNNB1 protein P35222 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 18316399 YES Simone Vumbaca Together, these results suggest that B-Cat increases MyoD binding to E box elements SIGNOR-255653 SIGNOR-ScFSTTR Satellite: FST transcriptional regulation CTNNB1 protein P35222 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 9606 BTO:0000887 18316399 YES gcesareni We showed that beta-catenin interacts directly with myod, a basic helix-loop-helix transcription factor essential for muscle differentiation and enhances its binding to e box elements and transcriptional activity. SIGNOR-161113 SIGNOR-ScFSTTR Satellite: FST transcriptional regulation CTNNB1 protein P35222 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates activity binding 9606 23151663 YES gcesareni Upon wnt activation, cytoplasmic beta-catenin is stabilized and enters the nucleus, where it associates with transcription factors, notably tcf (t cell factor) and lef (lymphoid enhancer-binding factor), to regulate the transcription of target genes. Thus beta-catenin regulates gene expression by direct interaction with transcription factors such as lef-1, providing a molecular mechanism for the transmission of signals, from cell-adhesion components or wnt protein to the nucleus. SIGNOR-199378 SIGNOR-ScFSTTR Satellite: FST transcriptional regulation CTNNB1 protein P35222 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates activity binding 9606 21078818 YES gcesareni Phosphorylated lrp5/6 leads to inhibition of the so-called beta-catenin destruction complex (which includes axin, gsk3, dvl, ck1, and the tumor suppressor adenomatous polyposis coli), resulting in the stabilization and translocation of beta-catenin in the nucleus, where it activates target genes through binding to tcf/lef transcription factors. SIGNOR-169632 SIGNOR-ScFSTTR Satellite: FST transcriptional regulation CTNNB1 protein P35222 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates activity binding 9606 BTO:0000782 15735151 YES gcesareni Activated dvl binds and inhibits the phosphorylation of beta catenin by gsk3beta/alfa, blocking beta catenin degradation), so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1 SIGNOR-134219 SIGNOR-ScFSTTR Satellite: FST transcriptional regulation MYOD1 protein P15172 UNIPROT FST protein P19883 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 15130492 NO lperfetto MyoD, CREB, and NFAT Mediate the Transcriptional Activation of the Follistatin Promoter Induced by TSA SIGNOR-251727 SIGNOR-ScFSTTR Satellite: FST transcriptional regulation MYOD1 protein P15172 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 NO lperfetto The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop-helix (bHLH) motif that mediates dimerization and dna binding. [...] myogenic bHLH proteins form heterodimers with ubiquitous bHLH proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. SIGNOR-37458 SIGNOR-ScFSTTR Satellite: FST transcriptional regulation MYF5 protein P13349 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 NO miannu The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop--helix (bhlh) motif that mediates dimerization and dna binding. / myogenic bhlh proteins form heterodimers with ubiquitous bhlh proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. SIGNOR-37409 SIGNOR-ScIFNG Satellite: IFN gamma MYOG protein P15173 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0000887 8288123 NO lperfetto The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop--helix (bhlh) motif that mediates dimerization and dna binding. / myogenic bhlh proteins form heterodimers with ubiquitous bhlh proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enancers. SIGNOR-37461 SIGNOR-ScIFNG Satellite: IFN gamma MYOG protein P15173 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0001103 28163303 NO apalma During early stages of myogenesis, CIITA binds directly to myogenin (MYOG) and inactivates it, preventing MYOG-mediated induction of myogenic genes that are required for muscle differentiation and function SIGNOR-255112 SIGNOR-ScIFNG Satellite: IFN gamma MYOG protein P15173 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates activity BTO:0001103 7532173 NO Simone Vumbaca These results suggest that at least initially, the muscle-forming regions contained cells with myogenic potential, and that this potential is lost in the myogenin mutants as development proceeds. SIGNOR-255644 SIGNOR-ScIFNG Satellite: IFN gamma IFNG protein P01579 UNIPROT IFNGR2 protein P38484 UNIPROT up-regulates binding 9606 7673114 YES gcesareni Ifn-g Binds to the ifn-g Receptor binding subunit (ifn-gR1;receptor chain 1), a species-specific cell surface transmembrane receptor chain (41, 42). A second transmembrane protein (ifn-gR2) (43 45) is required for signal transduction SIGNOR-31013 SIGNOR-ScIFNG Satellite: IFN gamma IFNG protein P01579 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates binding 9606 10986460 YES fspada Molecular interactions among cytokines and cytokine receptors form the basis of many cell-signaling pathways relevant to immune function. Interferon-g (ifng) signals through a multimeric receptor complex consistingof two different but structurally related transmembrane chains: the high-affinityreceptor-binding subunit (ifn-gra) and a species-specific accessory factor (af-1 or ifn-grb). SIGNOR-81804 SIGNOR-ScIFNG Satellite: IFN gamma IFNG protein P01579 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates binding 9606 12438563 YES gcesareni Ifn-g Binds to the ifn-g Receptor binding subunit (ifn-gR1;receptor chain 1), a species-specific cell surface transmembrane receptor chain (41, 42). A second transmembrane protein (ifn-gR2) (4345) is required for signal transduction SIGNOR-95626 SIGNOR-ScIFNG Satellite: IFN gamma IFNG protein P01579 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates activity binding 9606 BTO:0000801 23898330 YES lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249484 SIGNOR-ScIFNG Satellite: IFN gamma JAK2 protein O60674 UNIPROT IFNGR2 protein P38484 UNIPROT up-regulates activity binding 9606 BTO:0000801 23898330 YES lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249489 SIGNOR-ScIFNG Satellite: IFN gamma JAK2 protein O60674 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation 9606 BTO:0001103 21576360 YES When IFN-γ binds to its receptor, the receptor-associated protein tyrosine kinases Janus kinase I (JAK1) and JAK2 are activated (37). This leads to the phosphorylation of STAT1, which then dimerizes, translocates to the nucleus, and activates its target promoters, including the pIV promoter of Ciita SIGNOR-256248 SIGNOR-ScIFNG Satellite: IFN gamma JAK2 protein O60674 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000567 15322115 YES lperfetto Phosphorylation at tyr701 by the janus family of tyrosine kinases (jak) leads to stat1 dimerization via its src homology 2 domains, exposure of a dimer-specific nuclear localization signal, and subsequent nuclear translocation. SIGNOR-235709 SIGNOR-ScIFNG Satellite: IFN gamma JAK2 protein O60674 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 23898330 YES lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249490 SIGNOR-ScIFNG Satellite: IFN gamma IFNGR1 protein P15260 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 15864272 YES gcesareni The only type ii ifn, ifn-g, binds a distinct cell-surface receptor, which is known as the type ii ifn receptor. This receptor is also composed of two subunits, ifngr1 and ifngr2, which are associated with jak1 and jak2, respectively. Activation of the jaks that are associated with the type i ifn receptor results in tyrosine phosphorylation of stat2 SIGNOR-135952 SIGNOR-ScIFNG Satellite: IFN gamma IFNGR1 protein P15260 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 17063185 YES flangone Interferon- (ifn;type ii ifn) induces reorganization of the ifn-receptor subunits, ifngr1 and ifngr2, activating the janus kinases jak1 and jak2, which are constitutively associated with each subunit, respectively SIGNOR-150194 SIGNOR-ScIFNG Satellite: IFN gamma IFNGR1 protein P15260 UNIPROT JAK2 protein O60674 UNIPROT up-regulates binding 9606 15864272 YES gcesareni The only type ii ifn, ifn-, binds a distinct cell-surface receptor, which is known as the type ii ifn receptor. This receptor is also composed of two subunits, ifngr1 and ifngr2, which are associated with jak1 and jak2, respectively. Activation of the jaks that are associated with the type i ifn receptor results in tyrosine phosphorylation of stat2 SIGNOR-135955 SIGNOR-ScIFNG Satellite: IFN gamma IFNGR1 protein P15260 UNIPROT JAK2 protein O60674 UNIPROT up-regulates binding 9606 17063185 YES flangone Interferon- (ifn;type ii ifn) induces reorganization of the ifn-receptor subunits, ifngr1 and ifngr2, activating the janus kinases jak1 and jak2, which are constitutively associated with each subunit, respectively SIGNOR-150197 SIGNOR-ScIFNG Satellite: IFN gamma IFNGR1 protein P15260 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity binding 9606 23898330 YES lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249505 SIGNOR-ScIFNG Satellite: IFN gamma STAT1 protein P42224 UNIPROT CIITA protein P33076 UNIPROT up-regulates transcriptional regulation 9606 BTO:0001103 21576360 YES When IFN-γ binds to its receptor, the receptor-associated protein tyrosine kinases Janus kinase I (JAK1) and JAK2 are activated (37). This leads to the phosphorylation of STAT1, which then dimerizes, translocates to the nucleus, and activates its target promoters, including the pIV promoter of Ciita SIGNOR-256249 SIGNOR-ScIFNG Satellite: IFN gamma STAT1 protein P42224 UNIPROT CIITA protein P33076 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0001103 9551976 NO Federica Ferrentino A role for STAT1 in regulation of the CIITA promoter is shown by the rescue of IFN-gamma induction by expression of STAT1 in STAT1-defective U3A cells SIGNOR-255752 SIGNOR-ScIFNG Satellite: IFN gamma IFNGR2 protein P38484 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity binding 9606 BTO:0000801 23898330 YES lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249504 SIGNOR-ScIFNG Satellite: IFN gamma JAK1 protein P23458 UNIPROT IFNGR2 protein P38484 UNIPROT up-regulates activity phosphorylation 9606 19041276 YES lperfetto The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process. SIGNOR-249491 SIGNOR-ScIFNG Satellite: IFN gamma JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation 9606 21576360 YES When IFN-γ binds to its receptor, the receptor-associated protein tyrosine kinases Janus kinase I (JAK1) and JAK2 are activated (37). This leads to the phosphorylation of STAT1, which then dimerizes, translocates to the nucleus, and activates its target promoters, including the pIV promoter of Ciita SIGNOR-256247 SIGNOR-ScIFNG Satellite: IFN gamma JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS -1 7657660 YES lperfetto Stat1 was phosphorylated at tyr 701 in jak immune complex kinase reaction. The stat1 and stat2 proteins are present in the cytoplasm of untreated cells;upon stimulation with ifn-g, They become rapidly activated by tyrosine phosphorylation at a single site catalyzed by receptor associated jak (janus) kinases. SIGNOR-30905 SIGNOR-ScIFNG Satellite: IFN gamma JAK1 protein P23458 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 19041276 YES lperfetto The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process. SIGNOR-249488 SIGNOR-ScIFNG Satellite: IFN gamma CIITA protein P33076 UNIPROT MYOG protein P15173 UNIPROT down-regulates binding 9606 BTO:0001103 28163303 YES apalma During early stages of myogenesis, CIITA binds directly to myogenin (MYOG) and inactivates it, preventing MYOG-mediated induction of myogenic genes that are required for muscle differentiation and function SIGNOR-255111 SIGNOR-ScIFNG Satellite: IFN gamma MYOD1 protein P15172 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001103 12694204 YES Simone Vumbaca We conclude that MyoD is the major MRF that binds to the E-box from the myogenin promoter during differentiation. SIGNOR-255640 SIGNOR-ScIFNG Satellite: IFN gamma MYOD1 protein P15172 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 NO lperfetto We observed that the homeodomain factor pbx1, which cooperates with myod to stimulate myogenin expression, is constitutively bound to the myogenin promoter in a swi/snf-independent manner, suggesting a two-step mechanism in which myod initially interacts indirectly with the myogenin promoter and attracts chromatin-remodeling enzymes, which then facilitate direct binding by myod and other regulatory proteins. SIGNOR-135984 SIGNOR-ScIGF1R Satellite: IGF1R RPS6K proteinfamily SIGNOR-PF26 SIGNOR IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 BTO:0001103 21798082 YES lperfetto Negative feedback involves s6k, which inactivates irs by phosphorylation at multiple sites, thus inducing its degradation and altered cell localization. SIGNOR-252787 SIGNOR-ScIGF1R Satellite: IGF1R mTORC1 complex SIGNOR-C3 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr390 DSKFTRQtPVDSPDD 9606 11914378 YES azuccotti Thr229 phosphorylation requires prior phosphorylation of the Ser/Thr-Pro sites in the autoinhibitory domain and Thr389 in the linker domain [..]. Moreover, in vitro mTOR directly phosphorylates Ser371, and this event modulates Thr389phosphorylation by mTOR, compatible with earlier in vivo findings. SIGNOR-255842 SIGNOR-ScIGF1R Satellite: IGF1R mTORC1 complex SIGNOR-C3 SIGNOR Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates activity 10090 BTO:0002314 25047835 NO Knockdown (KD) of either mTORC or its subunit Raptor delayed SC activation without influencing the differentiation program. SIGNOR-256273 SIGNOR-ScIGF1R Satellite: IGF1R mTORC1 complex SIGNOR-C3 SIGNOR Cell_growth phenotype SIGNOR-PH33 SIGNOR up-regulates 9606 23863160 NO lperfetto Cellular energy and nutrient status will dictate whether mTORC1 takes over and drives cell growth or conversely whether AMPK becomes active once again to drive consecutive waves of autophagy thorough ULK1. SIGNOR-209919 SIGNOR-ScIGF1R Satellite: IGF1R PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15526160 YES miannu C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. SIGNOR-254950 SIGNOR-ScIGF1R Satellite: IGF1R AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 YES lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. These results indicate that phosphorylation by PKB/Akt negatively regulates FKHR1 by promoting export from the nucleus. SIGNOR-252346 SIGNOR-ScIGF1R Satellite: IGF1R AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser319 TFRPRTSsNASTISG 9606 11237865 YES lperfetto The transcription factor, forkhead in rhabdomyosarcoma (fkhr), is phosphorylated at three amino acid residues (thr-24, ser-256 and ser-319) by protein kinase b (pkb)alpha.Fkhr (forkhead in rhabdomyosarcoma), afx (all1 fused gene from chromosome x) and fkhrl1 (fkhr-like 1) are phosphorylated directly by pkb in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus SIGNOR-252349 SIGNOR-ScIGF1R Satellite: IGF1R AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 YES lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-252347 SIGNOR-ScIGF1R Satellite: IGF1R AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 10090 BTO:0002572 18423396 YES lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation SIGNOR-252350 SIGNOR-ScIGF1R Satellite: IGF1R AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 21440011 YES lperfetto Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs SIGNOR-252348 SIGNOR-ScIGF1R Satellite: IGF1R AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 10090 BTO:0000011 19593385 YES lperfetto In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis SIGNOR-252817 SIGNOR-ScIGF1R Satellite: IGF1R AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000887;BTO:0001103;BTO:0001760 20138985 YES lperfetto Pras40 is an insulin-regulated inhibitor of the mtorc1 protein kinase. Insulin stimulates akt/pkb-mediated phosphorylation of pras40, which prevents its inhibition of mtorc1 in cells and in vitro. Phosphorylation of pras40 on thr246 by pkb/akt facilitates efficient phosphorylation of ser183 by mtorc1. SIGNOR-217586 SIGNOR-ScIGF1R Satellite: IGF1R IRS1 protein P35568 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 20966354 YES lperfetto Irs proteins are capable of both regulating and activating pi3k, depending on the cell of origin. SIGNOR-252695 SIGNOR-ScIGF1R Satellite: IGF1R IRS1 protein P35568 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 10116 BTO:0001103 21798082 YES lperfetto Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate (pip2). SIGNOR-252694 SIGNOR-ScIGF1R Satellite: IGF1R FOXO1 protein Q12778 UNIPROT TRIM63 protein Q969Q1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21798082 NO lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. SIGNOR-235712 SIGNOR-ScIGF1R Satellite: IGF1R FOXO1 protein Q12778 UNIPROT TRIM63 protein Q969Q1 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18612045 NO lperfetto Transcriptional reporter assays performed in both HepG2 and C2C12 cells demonstrate that the MuRF1 promoter is highly responsive to dexamethasone-activated glucocorticoid receptor (GR) and FoxO1 individually, while co-overexpression of GR and FoxO1 leads to a dramatic synergistic increase in reporter activity SIGNOR-235367 SIGNOR-ScIGF1R Satellite: IGF1R FOXO1 protein Q12778 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21798082 NO lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. SIGNOR-236540 SIGNOR-ScIGF1R Satellite: IGF1R CCN4 protein O95388 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 10116 11782444 YES Here it is shown that WISP-1 can activate the antiapoptotic Akt/PKB signaling pathway. SIGNOR-256269 SIGNOR-ScIGF1R Satellite: IGF1R FBXO32 protein Q969P5 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 25096180 NO Muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx)/atrogin-1 were identified more than 10 years ago as two muscle-specific E3 ubiquitin ligases that are increased transcriptionally in skeletal muscle under atrophy-inducing conditions, making them excellent markers of muscle atrophy SIGNOR-252072 SIGNOR-ScIGF1R Satellite: IGF1R FBXO32 protein Q969P5 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates activity 10090 25549588 NO areggio Muscle-specific ubiq- uitin ligases, muscle-specific RING-finger 1 (MURF1; also known as TRIM63)12 and atrogin 1 (also known as MAFBX)8, are markedly induced in almost all types of atrophy. SIGNOR-254994 SIGNOR-ScIGF1R Satellite: IGF1R FBXO32 protein Q969P5 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 BTO:0001103 11717410 NO Atrogin-1 is one of the few examples of an F-box protein or Ub-protein ligase (E3) expressed in a tissue-specific manner and appears to be a critical component in the enhanced proteolysis leading to muscle atrophy in diverse diseases SIGNOR-255344 SIGNOR-ScIGF1R Satellite: IGF1R CTNNB1 protein P35222 UNIPROT CCN4 protein O95388 UNIPROT up-regulates quantity transcriptional regulation 10116 BTO:0002409 10716946 YES This study identifies WISP-1 as a beta-catenin-regulated gene that can contribute to tumorigenesis. The promoter of WISP-1 was cloned and shown to be activated by both Wnt-1 and beta-catenin expression. SIGNOR-256270 SIGNOR-ScIGF1R Satellite: IGF1R TRIM63 protein Q969Q1 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates activity 10090 25549588 NO areggio Muscle-specific ubiq- uitin ligases, muscle-specific RING-finger 1 (MURF1; also known as TRIM63)12 and atrogin 1 (also known as MAFBX), are markedly induced in almost all types of atrophy. SIGNOR-254993 SIGNOR-ScIGF1R Satellite: IGF1R IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr1179 GLENGLNyIDLDLVK 9606 17827393 YES gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). SIGNOR-157730 SIGNOR-ScIGF1R Satellite: IGF1R IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr1229 SSEDLSAyASISFQK 9606 17827393 YES gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). SIGNOR-157734 SIGNOR-ScIGF1R Satellite: IGF1R IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr465 GEEELSNyICMGGKG 9606 17827393 YES gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). SIGNOR-157738 SIGNOR-ScIGF1R Satellite: IGF1R IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr612 TLHTDDGyMPMSPGV 9606 17827393 YES gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). SIGNOR-157742 SIGNOR-ScIGF1R Satellite: IGF1R IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr632 GRKGSGDyMPMSPKS 9606 17827393 YES gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). SIGNOR-157746 SIGNOR-ScIGF1R Satellite: IGF1R IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr896 EPKSPGEyVNIEFGS 9606 17827393 YES gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). SIGNOR-157750 SIGNOR-ScIGF1R Satellite: IGF1R IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr941 EETGTEEyMKMDLGP 9606 17827393 YES gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). SIGNOR-157754 SIGNOR-ScIGF1R Satellite: IGF1R IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr989 VPSSRGDyMTMQMSC 9606 17827393 YES gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). SIGNOR-157758 SIGNOR-ScIGF1R Satellite: IGF1R IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation 9606 BTO:0001103 15829723 YES apalma IGF-I binding to its receptor activates the kinase activity of the receptor, which then recruits the insulin response substrate-1, causing activation of phosphatidyl-inositol-3 kinase (PI3K) to phosphorylate Akt. SIGNOR-255104 SIGNOR-ScIGF1R Satellite: IGF1R IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation 9606 21798082 YES gcesareni Binding of IGF1 to its receptor leads to activation of its intrinsic tyrosine kinase and autophosphorylation, thus generating docking sites for insulin receptor substrate (IRS), which is also phosphorylated by the IGF1 receptor. SIGNOR-175665 SIGNOR-ScIGF1R Satellite: IGF1R IGF1 protein P05019 UNIPROT IGF1R protein P08069 UNIPROT up-regulates binding 9606 19029956 YES lperfetto At the cellular level, the ligands IGF1, IGF2 and insulin bind to various members of the insulin receptor (IR) - IGF1 receptor (IGF1R) family. SIGNOR-182484 SIGNOR-ScIGF1R Satellite: IGF1R IGF1 protein P05019 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity binding 9606 21798082 YES lperfetto Binding of IGF1 to its receptor leads to activation of its intrinsic tyrosine kinase and autophosphorylation, thus generating docking sites for insulin receptor substrate (IRS), which is also phosphorylated by the IGF1 receptor. SIGNOR-175662 SIGNOR-ScIL1SEC Satellite: IL1 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates 9606 BTO:0001103 20219869 YES apalma Furthermore, NF-kB activation can cause destabilization of MyoD mRNA and degradation of MyoD protein (35, 49), which would further impede muscle differentiation SIGNOR-255352 SIGNOR-ScIL1SEC Satellite: IL1 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCL2 protein P13500 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 20219869 NO apalma Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6. SIGNOR-255356 SIGNOR-ScIL1SEC Satellite: IL1 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 20219869 NO apalma Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6. SIGNOR-255357 SIGNOR-ScIL1SEC Satellite: IL1 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR IL1B protein P01584 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 20219869 NO apalma Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6. SIGNOR-255355 SIGNOR-ScIL1SEC Satellite: IL1 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR NOS2 protein P35228 UNIPROT up-regulates transcriptional regulation BTO:0001103 20219869 NO Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6. SIGNOR-256250 SIGNOR-ScIL1SEC Satellite: IL1 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCND1 protein P24385 UNIPROT up-regulates quantity by expression 9606 BTO:0001103 20219869 YES apalma Importantly, NF-kB can promote the expression and stability of cyclin D1 in muscle (4, 35, 39, 132), leading to increased cell proliferation and inhibition of differentiation. SIGNOR-255358 SIGNOR-ScIL1SEC Satellite: IL1 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR TNF protein P01375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 20219869 NO apalma Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6. SIGNOR-255354 SIGNOR-ScIL1SEC Satellite: IL1 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 11359934 NO gcesareni The nuclear factor-kappaB (NF-kappaB) family of transcription factors has been shown to regulate proliferation in several cell types. SIGNOR-245043 SIGNOR-ScIL1SEC Satellite: IL1 IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 9346241 YES lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-216385 SIGNOR-ScIL1SEC Satellite: IL1 IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 9346241 YES lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-216389 SIGNOR-ScIL1SEC Satellite: IL1 IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation 9606 21232017 YES lperfetto Tak1 become activated and then phosphorilates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation SIGNOR-216396 SIGNOR-ScIL1SEC Satellite: IL1 IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 BTO:0000567 9346241 YES lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-209773 SIGNOR-ScIL1SEC Satellite: IL1 IKK-complex complex SIGNOR-C14 SIGNOR IKK-complex complex SIGNOR-C14 SIGNOR down-regulates phosphorylation 9606 10195894 YES lperfetto Once activated, ikkbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased ikk activity and may prevent prolonged activation of the inflammatory response SIGNOR-216373 SIGNOR-ScIL1SEC Satellite: IL1 IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 BTO:0000007 19609947 YES lperfetto Our data suggest that the stimulation of nfkb by akt is dependent on the phosphorylation of p65 at s534, mediated by ikk (ikb kinase) alfa and beta. SIGNOR-216365 SIGNOR-ScIL1SEC Satellite: IL1 IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 15489227 YES lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. SIGNOR-216341 SIGNOR-ScIL1SEC Satellite: IL1 TRAF6 protein Q9Y4K3 UNIPROT TAB2 protein Q9NYJ8 UNIPROT up-regulates activity binding 9606 25290089 YES lperfetto The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex. SIGNOR-205458 SIGNOR-ScIL1SEC Satellite: IL1 CCND1 protein P24385 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 9606 BTO:0001103 20219869 NO apalma Importantly, NF-kB can promote the expression and stability of cyclin D1 in muscle (4, 35, 39, 132), leading to increased cell proliferation and inhibition of differentiation. SIGNOR-255351 SIGNOR-ScIL1SEC Satellite: IL1 CCND1 protein P24385 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18177723 NO andrea cerquone perpetuini Cyclin D1 is necessary for proliferation of different cell types, including myogenic cells. SIGNOR-255412 SIGNOR-ScIL1SEC Satellite: IL1 MYD88 protein Q99836 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity binding 10090 BTO:0003432 10217414 YES lperfetto Interleukin-1 (il-1) stimulates the association of the il-1 receptor-associated protein kinase (irak) with the heterodimer of il-iri and il-iracp via the adapter protein myd88. Myd88 binds to both irak (il-1 receptor-associated kinase) and the heterocomplex (the signaling complex) of the two receptor chains and thereby mediates the association of irak with the receptor. SIGNOR-67143 SIGNOR-ScIL1SEC Satellite: IL1 IL1B protein P01584 UNIPROT IL1R1 protein P14778 UNIPROT up-regulates binding 9606 BTO:0001253 9625767 YES gcesareni Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab). SIGNOR-58122 SIGNOR-ScIL1SEC Satellite: IL1 IL1B protein P01584 UNIPROT IL1R1 protein P14778 UNIPROT up-regulates activity binding 9606 BTO:0000801 24166242 YES lperfetto Pro-IL-1beta, mIL-1beta and mIL-beta all bind to IL-1RI, which recruits the IL-1 receptor accessory protein (IL-1RAcP) as a co-receptor. SIGNOR-249511 SIGNOR-ScIL1SEC Satellite: IL1 IL1R1 protein P14778 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity 9606 BTO:0000007 14625308 NO lperfetto Formation of the signaling il-1 receptor complex results in the activation and hyperphosphorylation of irak-1. SIGNOR-119208 SIGNOR-ScIL1SEC Satellite: IL1 IL1R1 protein P14778 UNIPROT MYD88 protein Q99836 UNIPROT up-regulates activity binding 9606 BTO:0003432 10217414 YES lperfetto Interleukin-1 (il-1) stimulates the association of the il-1 receptor-associated protein kinase (irak) with the heterodimer of il-iri and il-iracp via the adapter protein myd88. SIGNOR-67140 SIGNOR-ScIL1SEC Satellite: IL1 MAP3K7 protein O43318 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates activity phosphorylation 9606 21232017 YES lperfetto Tak1 become activated and then phosphorilates and activates ikk2 whic in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. SIGNOR-209759 SIGNOR-ScIL1SEC Satellite: IL1 TAB2 protein Q9NYJ8 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 8638164 YES lperfetto The yeast two-hybrid system has now revealed two human proteins, termed tab1 and tab2 (for tak1 binding protein), that interact with tak1. Overproduction of tab1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by tgf-beta, and increased the kinase activity of tak1. . These results define tab2 as an adaptor linking tak1 and traf6 and as a mediator of tak1 activation in the il-1 signaling pathway . taken together, these results indicate that polyubiquitination of rip1 mediates the independent recruitment of tab2 and nemo, which in turn recruits tak1 and ikk, respectively, to tnf-r1. SIGNOR-105860 SIGNOR-ScIL1SEC Satellite: IL1 TAB2 protein Q9NYJ8 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 14633987 YES lperfetto These results suggest that TAB2 and TAB3 function redundantly as mediators of TAK1 activation in IL-1 and TNF signal transduction. SIGNOR-119370 SIGNOR-ScIL1SEC Satellite: IL1 TAB2 protein Q9NYJ8 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 14670075 YES lperfetto Our results indicate that two distinct TAK1 complexes are present in cells. One comprises TAK1 complexed with TAB1 and TAB2, and the other TAK1 complexed with TAB1 and TAB3. Both complexes are activated in response to tumour necrosis factor-alpha or interleukin-1 in human epithelial KB cells or bacterial lipopolysaccharide in RAW264.7 macrophages SIGNOR-120268 SIGNOR-ScIL1SEC Satellite: IL1 MYOD1 protein P15172 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 NO lperfetto The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop-helix (bHLH) motif that mediates dimerization and dna binding. [...] myogenic bHLH proteins form heterodimers with ubiquitous bHLH proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. SIGNOR-37458 SIGNOR-ScIL1SEC Satellite: IL1 IRAK1 protein P51617 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0000007 8837778 YES lperfetto Il-1 treatment of 293 cells induces the association of traf6 with irak. SIGNOR-44234 SIGNOR-ScIL1SEC Satellite: IL1 IRAK1 protein P51617 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 12242293 YES lperfetto We now find that the phosphorylated IRAK in turn recruits TRAF6 to the receptor complex (complex I), which differs from the previous concept that IRAK interacts with TRAF6 after it leaves the receptor. IRAK then brings TRAF6 to TAK1 SIGNOR-92994 SIGNOR-ScIL1SEC Satellite: IL1 IL1A protein P01583 UNIPROT IL1R1 protein P14778 UNIPROT up-regulates activity binding 9606 BTO:0000876 7964161 YES lperfetto Interleukin-1 receptor (il-1r) is a cytokine receptor which binds interleukin 1. SIGNOR-35077 SIGNOR-ScIL1SEC Satellite: IL1 IL1A protein P01583 UNIPROT IL1R1 protein P14778 UNIPROT up-regulates activity binding 9606 BTO:0001573 9565970 YES lperfetto Il-1ri is responsible for il-1 signaling SIGNOR-56718 SIGNOR-ScIL1SEC Satellite: IL1 NFKBIA protein P25963 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 1340770 YES lperfetto Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b SIGNOR-217394 SIGNOR-ScIL1SEC Satellite: IL1 NFKBIA protein P25963 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 9914500 YES lperfetto In nonstimulated cells, nf-kappab is present in the cytosol where it is complexed to its inhibitor ikappab however, we found that only one of the activities, namely the ikk1/2 complex, exists as a pre-assembled kinase-substrate complex in which the ikks are directly or indirectly associated with several nf-kappab-related and ikappab-related proteins: rela, relb, crel, p100, p105, ikappa balpha, ikappa bbeta and ikappa bepsilon. SIGNOR-64092 SIGNOR-ScIL6 Satellite: IL6 SOCS3 protein O14543 UNIPROT JAK1 protein P23458 UNIPROT down-regulates activity binding 9606 23454976 YES miannu SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition SIGNOR-253051 SIGNOR-ScIL6 Satellite: IL6 SOCS1 protein O15524 UNIPROT JAK1 protein P23458 UNIPROT down-regulates binding 9606 23663276 YES milica Socs1 and socs3 target jak1 and gp130, respectively, near the plasma membrane to prevent cytoplasmic stats from being activated, whereas pias1 principally targets activated stat1 in the cell nucleus and prevents it from binding to dna. SIGNOR-202042 SIGNOR-ScIL6 Satellite: IL6 SOCS1 protein O15524 UNIPROT JAK1 protein P23458 UNIPROT down-regulates binding 9606 11133764 YES gcesareni Jab/socs1/ssi-1 is an il-2 induced inhibitor of il-2 signaling that functions by inhibiting jak kinase activity SIGNOR-85352 SIGNOR-ScIL6 Satellite: IL6 JAK2 protein O60674 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000599 9575217 YES lperfetto Activation of wild type stat3: il-6 treatment causes stat3 recruitment to receptor tyrosine phosphopeptides (gp130) where it is phosphorylated on tyrosine 705 (y) by jak kinase SIGNOR-236463 SIGNOR-ScIL6 Satellite: IL6 JAK2 protein O60674 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000599 9575217 YES lperfetto Inactive cytoplasmic STATs are recruited to the activated receptor by docking of the STAT SH2 domain to selected receptor tyrosine phosphopeptides, where they are in turn phosphorylated on a single tyrosine by Jak kinases. Has been identified tyrosine 705 of Stat3 as the likely site of phosphorylation by Jak kinases during signal transduction. SIGNOR-238638 SIGNOR-ScIL6 Satellite: IL6 IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 23663276 YES milica In classical il-6 signaling, the cytokine first binds to the membrane-bound il-6 receptor (il-6r;cd126) that is induced to associate with a homodimer of gp130 which then transmits the intracellular signal. SIGNOR-202030 SIGNOR-ScIL6 Satellite: IL6 IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates activity binding 9606 18923185 YES miannu IL-6 and IL-11 are the only members of the family that signal via the induction of a gp130 homodimer after binding their specific -receptors, IL-6R and IL-11R. When IL-6 binds to the homodimerized IL-6Rα/gp130Rβ, it results in a signaling cascade that is initiated by the autophoshorylation and activation of JAK. SIGNOR-255324 SIGNOR-ScIL6 Satellite: IL6 JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 19723038 YES lperfetto The activation of stat-3 is regulated by phosphorylation of tyrosine 705 by receptor and nonreceptor protein tyrosine kinases. These include epidermal growth factor receptor (egfr) kinase, src, janus-activated kinases (jak), and extracellular signal-regulated kinase (erk). SIGNOR-187775 SIGNOR-ScIL6 Satellite: IL6 JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity binding 9606 24710148 YES lperfetto The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3). SIGNOR-236369 SIGNOR-ScIL6 Satellite: IL6 JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 9606 26260587 YES IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes. SIGNOR-253590 SIGNOR-ScIL6 Satellite: IL6 STAT3 protein P40763 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 25194572 NO miannu Here we show that IL-6-activated Stat3 signaling regulates satellite cell behavior, promoting myogenic lineage progression through myogenic differentiation 1 (Myod1) regulation. IL-6 stimulation promoted an increase in the mRNA levels of both Stat3 and Myod1. Stat3 mediated this effect, as IL-6‚Äìdependent Myod1 upregulation was impaired after infection with the shStat3 lentivirus. SIGNOR-255416 SIGNOR-ScIL6 Satellite: IL6 STAT3 protein P40763 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0002314 25194572 NO lperfetto STAT3 signaling controls satellite cell expansion and skeletal muscle repair SIGNOR-245048 SIGNOR-ScIL6 Satellite: IL6 MYOD1 protein P15172 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 NO lperfetto The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop-helix (bHLH) motif that mediates dimerization and dna binding. [...] myogenic bHLH proteins form heterodimers with ubiquitous bHLH proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. SIGNOR-37458 SIGNOR-ScIL6 Satellite: IL6 IL6R protein P08887 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 23663276 YES milica In classical il-6 signaling, the cytokine first binds to the membrane-bound il-6 receptor (il-6r;cd126) that is induced to associate with a homodimer of gp130 which then transmits the intracellular signal. SIGNOR-202033 SIGNOR-ScIL6 Satellite: IL6 IL6R protein P08887 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation 9606 23869758 YES miannu On binding of IL-6 to its receptor IL-6R, JAK2 is phosphorylated, then STAT3 is phosphorylated by JAK2 SIGNOR-254405 SIGNOR-ScIL6 Satellite: IL6 IL6ST protein P40189 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity phosphorylation Ser659 WPNVPDPsKSHIAQW -1 8511589 YES lperfetto The biological functions of interleukin-6 (IL-6) are mediated through a signal-transducing component of the IL-6 receptor, gp130, which is associated with the ligand-occupied IL-6 receptor (IL-6R) protein. Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130. Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein. Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130. SIGNOR-238621 SIGNOR-ScIL6 Satellite: IL6 IL6ST protein P40189 UNIPROT JAK1 protein P23458 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 23663276 YES milica Il-6 family members typically signal through the common gp130 receptor, with the janus kinase/signal transducer and activator of transcription (jak/stat) pathway being the major intracellular mediator of their effects. SIGNOR-202036 SIGNOR-ScIL6 Satellite: IL6 IL6ST protein P40189 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 24710148 YES milica The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3). SIGNOR-204841 SIGNOR-ScMTC Satellite: Myogenic transcriptional cascade PAX7 protein P23759 UNIPROT MYF5 protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 18066051 YES Simone Vumbaca Together, these experiments indicate that Pax7 enforces satellite cell commitment by recruiting a HMT complex to Myf5, resulting in transcriptional activation. SIGNOR-255641 SIGNOR-ScMTC Satellite: Myogenic transcriptional cascade PAX7 protein P23759 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates quantity by destabilization 10090 17548510 NO Simone Vumbaca Previously, we showed that Pax7 overexpression in adult primary myoblasts down-regulates MyoD and prevents myogenin induction, inhibiting myogenesis. We show that Pax7 prevents muscle differentiation independently of its transcriptional activity, affecting MyoD function. [...] Pax7 expression affects MyoD protein stability SIGNOR-255637 SIGNOR-ScMTC Satellite: Myogenic transcriptional cascade PAX7 protein P23759 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18854138 NO lperfetto Our cell-based assays and in vitro studies reveal a tight codependent partnership between foxo3 and pax3/7 to coordinately recruit rna polymerase ii and form a preinitiation complex (pic) to activate myod transcription in myoblasts. SIGNOR-181624 SIGNOR-ScMTC Satellite: Myogenic transcriptional cascade MYOG protein P15173 UNIPROT MYF6 protein P23409 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001103 7739551 YES Simone Vumbaca [...] confirming that myogenin binds to the E1 and E2 E boxes located in close proximity to the MRF4 transcription start site. SIGNOR-255642 SIGNOR-ScMTC Satellite: Myogenic transcriptional cascade MYOG protein P15173 UNIPROT PAX7 protein P23759 UNIPROT down-regulates quantity by destabilization 10090 BTO:0004058 17548510 NO Simone Vumbaca Indeed, we observed a reduction in Pax7 protein levels upon ectopic myogenin expression in MM14 myoblasts, even under proliferation conditions SIGNOR-255638 SIGNOR-ScMTC Satellite: Myogenic transcriptional cascade MYOG protein P15173 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates activity BTO:0001103 7532173 NO Simone Vumbaca These results suggest that at least initially, the muscle-forming regions contained cells with myogenic potential, and that this potential is lost in the myogenin mutants as development proceeds. SIGNOR-255644 SIGNOR-ScMTC Satellite: Myogenic transcriptional cascade MYF6 protein P23409 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates activity BTO:0001103 7532173 NO Simone Vumbaca Finally, MRF4 may be responsible for the final myogenic events of the fully differentiated myofiber SIGNOR-255645 SIGNOR-ScMTC Satellite: Myogenic transcriptional cascade MYF6 protein P23409 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 NO miannu The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop--helix (bhlh) motif that mediates dimerization and dna binding. / myogenic bhlh proteins form heterodimers with ubiquitous bhlh proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. SIGNOR-37455 SIGNOR-ScMTC Satellite: Myogenic transcriptional cascade MEF2D protein Q14814 UNIPROT MYF6 protein P23409 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165;BTO:0000222 7739551 YES lperfetto Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis. SIGNOR-238715 SIGNOR-ScMTC Satellite: Myogenic transcriptional cascade MEF2C protein Q06413 UNIPROT MYF6 protein P23409 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165;BTO:0000222 7739551 YES lperfetto Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis. SIGNOR-238652 SIGNOR-ScMTC Satellite: Myogenic transcriptional cascade MYOD1 protein P15172 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001103 15870273 YES Simone Vumbaca We suggest that the interaction between MyoD and Pbx is necessary to initially target MyoD to the myogenin promoter SIGNOR-255639 SIGNOR-ScMTC Satellite: Myogenic transcriptional cascade MYOD1 protein P15172 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001103 12694204 YES Simone Vumbaca We conclude that MyoD is the major MRF that binds to the E-box from the myogenin promoter during differentiation. SIGNOR-255640 SIGNOR-ScMTC Satellite: Myogenic transcriptional cascade MYF5 protein P13349 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates activity BTO:0001103 17495111 NO Simone Vumbaca In summary, the absence of Myf5 clearly reduced the initial expansion of satellite cell-derived transient amplifying cells and resulted in a shift of the ratio of satellite cell subpopulations but did not affect the specification and generation of specific subpopulations of satellite cell-derived cells such as reserve cells, amplifying cells, and differentiating mature myogenic cells. SIGNOR-255643 SIGNOR-ScMTC Satellite: Myogenic transcriptional cascade MEF2A protein Q02078 UNIPROT MYF6 protein P23409 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 7739551 YES lperfetto Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis. SIGNOR-238709 SIGNOR-ScNOTCH Satellite: NOTCH NOTCH proteinfamily SIGNOR-PF30 SIGNOR RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding BTO:0001103 7566092 YES svumbaca Here we show that activated forms of mNotch associate with the human analogue of Su(H), KBF2/RBP-Jk and act as transcriptional activators through the KBF2-binding sites of the HES-1 promoter. SIGNOR-255363 SIGNOR-ScNOTCH Satellite: NOTCH NOTCH proteinfamily SIGNOR-PF30 SIGNOR RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding BTO:0001103 22045613 YES svumbaca NICD is translocated to the nucleus where it binds recombining binding protein-Jj (RBP-Jj) SIGNOR-255364 SIGNOR-ScNOTCH Satellite: NOTCH NOTCH proteinfamily SIGNOR-PF30 SIGNOR RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding 23729744 YES apalma The released NICD translocates directly to the nucleus, where it forms a transcriptional complex with the DNA-binding protein CSL (CBF1, Suppressor of Hairless, Lag1), Mastermind (Mam) and transcriptional co-activators to drive the expression of Notch target genes SIGNOR-255377 SIGNOR-ScNOTCH Satellite: NOTCH NOTCH proteinfamily SIGNOR-PF30 SIGNOR RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding BTO:0001103 12361602 YES apalma Notch is cleaved and translocates to the nucleus, where it activates a family of transcription factors, exemplified by Suppressor of Hairless and CBF/RJBk SIGNOR-255380 SIGNOR-ScNOTCH Satellite: NOTCH NOTCH proteinfamily SIGNOR-PF30 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates BTO:0001103 12361602 NO apalma Taken together, these results show that Notch-1 activity promotes myogenic cell proliferation and that attenuation of Notch-1 activity by its antagonist Numb causes cells to exit from the cell cycle, express MRFs, and undergo myogenic differentiation. SIGNOR-255376 SIGNOR-ScNOTCH Satellite: NOTCH RBPJ/NOTCH complex SIGNOR-C97 SIGNOR HEY1 protein Q9Y5J3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 21193018 YES lperfetto Activated NICD-RBP-Jk complex displaces co-repressors and recruits coactivator (co-A) mediating the transcription of target genes such as Hes-1 (hairy enhancer of split), cyclin D, Hey-1 (hairy/enhancer-of-split related with YRPW motif) and others [1213]. SIGNOR-170854 SIGNOR-ScNOTCH Satellite: NOTCH RBPJ/NOTCH complex SIGNOR-C97 SIGNOR DUSP1 protein P28562 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0001103 17158101 NO Andrea Our results show that Notch specifically induces expression of MKP-1, a member of the dual-specificity MAPK phosphatase, which directly inactivates p38 to negatively regulate C2C12 myogenesis SIGNOR-255744 SIGNOR-ScNOTCH Satellite: NOTCH RBPJ/NOTCH complex SIGNOR-C97 SIGNOR HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7566092 YES lperfetto Here we show that activated forms of mNotch associate with the human analogue of Su(H), KBF2/RBP-J kappa (refs 8,9) and act as transcriptional activators through the KBF2-binding sites of the HES-1 promoter. SIGNOR-209590 SIGNOR-ScNOTCH Satellite: NOTCH RBPJ/NOTCH complex SIGNOR-C97 SIGNOR PAX7 protein P23759 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103;BTO:0002314 22493066 YES lperfetto Constitutive Notch Activation Upregulates Pax7 and Promotes the Self-Renewal of Skeletal Muscle Satellite Cells NICD regulates Pax7 through interaction with RBP-J_, which binds to two consensus sites upstream of the Pax7 gene. SIGNOR-219365 SIGNOR-ScNOTCH Satellite: NOTCH RBPJ/NOTCH complex SIGNOR-C97 SIGNOR PAX7 protein P23759 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001103 22493066 NO svumbaca Both binding sites were enriched by more than 5-fold in the ChIP assay with RBP-Jk antibody, suggesting that RBP-Jk occupies these sequences in the Pax7 promoter region. SIGNOR-255365 SIGNOR-ScNOTCH Satellite: NOTCH PAX7 protein P23759 UNIPROT Quiescence phenotype SIGNOR-PH25 SIGNOR up-regulates BTO:0001103 15501225 NO svumbaca Our work presented here provides a possible mechanism involving Pax-7 that allow satellite cells to exit the cell cycle, down-regulate MyoD, and prevent myogenin induction, phenotypes characteristic of the quiescent satellite cell. SIGNOR-255366 SIGNOR-ScNOTCH Satellite: NOTCH PAX7 protein P23759 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 9606 BTO:0001103;BTO:0002314 22493066 NO lperfetto Constitutive Notch Activation Upregulates Pax7 and Promotes the Self-Renewal of Skeletal Muscle Satellite Cells SIGNOR-219371 SIGNOR-ScNOTCH Satellite: NOTCH RBPJ protein Q06330 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding 23729744 YES apalma The released NICD translocates directly to the nucleus, where it forms a transcriptional complex with the DNA-binding protein CSL (CBF1, Suppressor of Hairless, Lag1), Mastermind (Mam) and transcriptional co-activators to drive the expression of Notch target genes SIGNOR-255378 SIGNOR-ScNOTCH Satellite: NOTCH RBPJ protein Q06330 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding 12361602 YES apalma Notch is cleaved and translocates to the nucleus, where it activates a family of transcription factors, exemplified by Suppressor of Hairless and CBF/RJBk SIGNOR-255379 SIGNOR-ScNOTCH Satellite: NOTCH RBPJ protein Q06330 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates quantity by repression transcriptional regulation 23729744 NO apalma In the absence of NICD, CSL forms complexes with a variety of co-repressors to suppress the transcription of Notch target genes SIGNOR-255373 SIGNOR-ScNOTCH Satellite: NOTCH DLL1 protein O00548 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding BTO:0001103 12361602 YES apalma When activated by its ligands (Delta and Jagged in vertebrates and Serrate in invertebrates), the intracellular portion of Notch is cleaved and translocates to the nucleus SIGNOR-255368 SIGNOR-ScNOTCH Satellite: NOTCH DLL1 protein O00548 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 23729744 YES apalma The NECD undergoes O-linked glycosylation during Notch synthesis and secretion, which is crucial for proper folding of the Notch receptor and the interaction with its ligand DSL (Delta, Serrate, Lag-2)(Rana and Haltiwanger, 2011). The Notch receptor on the signal-receiving cell binds directly to ligands located on the apposing signal-sending cell SIGNOR-255369 SIGNOR-ScNOTCH Satellite: NOTCH ADAM17 protein P78536 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates cleavage 10090 18344021 YES apalma Two ADAMs have been implicated in the S2 cleavage of Notch. In Drosophila, ADAM10 ortholog Kuzbanian is the main protease mediating Notch processing [35–38]. In mouse cells in vitro, ADAM17, and not ADAM10, appears to be a protease responsible for Notch cleavage SIGNOR-255370 SIGNOR-ScNOTCH Satellite: NOTCH ADAM17 protein P78536 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates cleavage 10090 23729744 YES apalma Receptor–ligand engagement triggers a second NECD cleavage (S2 cleavage) by a metalloproteinase ADAM (known as Kuzbanian in Drosophila melanogaster) SIGNOR-255371 SIGNOR-ScNOTCH Satellite: NOTCH HES1 protein Q14469 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000165 BTO:0000887 10066785 NO lperfetto Notch signaling up-regulated hes1 mrna expression within 1 h and subsequently reduced expression of myod mrna. SIGNOR-235596 SIGNOR-ScNOTCH Satellite: NOTCH NUMB protein P49757 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates BTO:0001103 12361602 YES apalma Numb is an inhibitor of Notch signaling that interacts with the intracellular portion of Notch and antagonizes its activity by preventing nuclear translocation SIGNOR-255374 SIGNOR-ScNOTCH Satellite: NOTCH NUMB protein P49757 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates BTO:0001103 12361602 YES apalma Therefore, these genetic data further support the hypothesis that activation of Notch-1 promotes a less committed myogenic phenotype and that the attenuation of Notch-1 activity by Numb promotes progression along the myogenic lineage toward a myoblast cell fate. SIGNOR-255375 SIGNOR-ScNOTCH Satellite: NOTCH DUSP1 protein P28562 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation 10090 17158101 YES gcesareni Our results show that Notch specifically induces expression of MKP-1, a member of the dual-specificity MAPK phosphatase, which directly inactivates p38 to negatively regulate C2C12 myogenesis. SIGNOR-236867 SIGNOR-ScNOTCH Satellite: NOTCH DUSP1 protein P28562 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation 9606 BTO:0000567 12356755 YES gcesareni Here we show that glucocorticoids synergistically enhance nthi-induced tlr2 expression via specific up-regulation of the mapk phosphatase-1 (mkp-1) that, in turn, leads to dephosphorylation and inactivation of p38 mapk, the negative regulator for tlr2 expression. SIGNOR-93873 SIGNOR-ScNOTCH Satellite: NOTCH DUSP1 protein P28562 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation 9606 20626350 YES lperfetto The activity of MAPKs can be also regulated by a family of DUSPs (dual-specificity phosphatases)/MKPs (MAPK phosphatases), which dephosphorylate both phosphotyrosine and phosphothreonine residues MKPs 1, 4, 5 and 7 can dephosphorylate p38_ and p38_ in addition to JNK MAPKs. Importantly, some MKPs are transcriptionally up-regulated by stimuli that activate MAPK signalling, and are thought to play an important role limiting the extent of MAPK activation SIGNOR-166571 SIGNOR-ScNOTCH Satellite: NOTCH MYOD1 protein P15172 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 NO lperfetto The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop-helix (bHLH) motif that mediates dimerization and dna binding. [...] myogenic bHLH proteins form heterodimers with ubiquitous bHLH proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. SIGNOR-37458 SIGNOR-ScNOTCH Satellite: NOTCH MAPK14 protein Q16539 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 15824134 NO Andrea Inhibition of p38 / MAPKs (a) promotes exit from the cell cycle, (b) prevents differentiation, and (c) insulates the cell from most external stimuli allowing the satellite cell to maintain a quiescent state. Activation of satellite cells and p38 / MAPKs occurs concomitantly, providing further support that these MAPKs function as a molecular switch for satellite cell activation SIGNOR-255745 SIGNOR-ScTNFA Satellite: TNFA NfKb-p65/p50 complex SIGNOR-C13 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates 9606 BTO:0001103 20219869 YES apalma Furthermore, NF-kB activation can cause destabilization of MyoD mRNA and degradation of MyoD protein (35, 49), which would further impede muscle differentiation SIGNOR-255352 SIGNOR-ScTNFA Satellite: TNFA NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 11359934 NO gcesareni The nuclear factor-kappaB (NF-kappaB) family of transcription factors has been shown to regulate proliferation in several cell types. SIGNOR-245043 SIGNOR-ScTNFA Satellite: TNFA Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR PAX7 protein P23759 UNIPROT down-regulates quantity by repression transcriptional regulation 20887952 YES The results presented above demonstrate a signal-dependent interaction between p38a, YY1, and EZH2 on the chromatin of the Pax7 regulatory elements that coincides with p38-mediated repression of Pax7 at early stages of myoblast differentiation. SIGNOR-253598 SIGNOR-ScTNFA Satellite: TNFA IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 BTO:0000567 9346241 YES lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-209773 SIGNOR-ScTNFA Satellite: TNFA IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 9346241 YES lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-216385 SIGNOR-ScTNFA Satellite: TNFA IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 9346241 YES lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-216389 SIGNOR-ScTNFA Satellite: TNFA IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation 9606 21232017 YES lperfetto Tak1 become activated and then phosphorilates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation SIGNOR-216396 SIGNOR-ScTNFA Satellite: TNFA TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT up-regulates activity binding 9606 17151142 YES miannu TNF-α has two distinct plasma membrane receptors known as p55 and p75. These data indicate that myogenic activation of p38 requires TNF-alpha receptor-mediated signaling SIGNOR-253591 SIGNOR-ScTNFA Satellite: TNFA TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT up-regulates activity binding 9606 23070005 YES miannu For TNFR1, the cytokine TNFα binds to the receptor and triggers its trimerization, which leads to the assembly of the receptor complex and initiation of signaling. SIGNOR-199091 SIGNOR-ScTNFA Satellite: TNFA TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates 9606 10795740 YES We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation SIGNOR-256252 SIGNOR-ScTNFA Satellite: TNFA PAX7 protein P23759 UNIPROT Quiescence phenotype SIGNOR-PH25 SIGNOR up-regulates BTO:0001103 15501225 NO svumbaca Our work presented here provides a possible mechanism involving Pax-7 that allow satellite cells to exit the cell cycle, down-regulate MyoD, and prevent myogenin induction, phenotypes characteristic of the quiescent satellite cell. SIGNOR-255366 SIGNOR-ScTNFA Satellite: TNFA RIPK1 protein Q13546 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates activity binding 10090 BTO:0000452 10795740 YES gcesareni We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation SIGNOR-245026 SIGNOR-ScTNFA Satellite: TNFA TRADD protein Q15628 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 8612133 YES lperfetto We show that tradd interacts strongly with rip;rip is a serinethreonine kinase that is recruited by tradd to tnfr1 in a tnf-dependent process. SIGNOR-40043 SIGNOR-ScTNFA Satellite: TNFA ZFP36 protein P26651 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 25815583 YES The TTP binding site in the 3′ UTR of MyoD would permit TTP-mediated mRNA decay SIGNOR-253597 SIGNOR-ScTNFA Satellite: TNFA TNFRSF1A protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 BTO:0000567 11672426 NO lperfetto Conversely, only activation of the TNFR1 could stimulate mitogen-activated protein kinase (MAPK) or p38 MAPK activities in a time-dependent manner. SIGNOR-226637 SIGNOR-ScTNFA Satellite: TNFA TNFRSF1A protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 11502070 YES lperfetto The death domain of tnfrsf1a provides a novel molecular interface that interacts specifically with the death domain of tradd. SIGNOR-109719 SIGNOR-ScTNFA Satellite: TNFA TNFRSF1A protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 10090 BTO:0002572;BTO:0000801 21232017 YES miannu TRADD and RIP1 contain a C‐terminal death domain which mediates binding to the death domain of TNFR1. Upon association with ligated TNFR1, TRADD further recruits the adapter protein TRAF2 via its N‐terminal TRAF‐binding domain SIGNOR-245029 SIGNOR-ScTNFA Satellite: TNFA TNFRSF1A protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 BTO:0000007 7758105 YES lperfetto We have identified a novel 34 kda protein, designated tradd, that specifically interacts with an intracellular domain of tnfr1 tradd interacts with the death domain of tnfrsf1a to initiate distinct signaling cascades for two of the most important biological activities of tnf, nf-kb activation and programmed cell death tradd, a novel protein that specifically interacts with the death domain of tnfr1 and activates signaling pathways for both of these activities when overexpressed. SIGNOR-32739 SIGNOR-ScTNFA Satellite: TNFA TNFRSF1A protein P19438 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates 9606 10795740 YES We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation SIGNOR-256251 SIGNOR-ScTNFA Satellite: TNFA YY1 protein P25490 UNIPROT Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR up-regulates quantity by expression 17158804 YES YY1 REPO domain is necessary and sufficient for PcG transcriptional repression, Polycomb recruitment to DNA, and methylation of histone H3 on lysine 27 SIGNOR-253595 SIGNOR-ScTNFA Satellite: TNFA MYOD1 protein P15172 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 NO lperfetto The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop-helix (bHLH) motif that mediates dimerization and dna binding. [...] myogenic bHLH proteins form heterodimers with ubiquitous bHLH proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. SIGNOR-37458 SIGNOR-ScTNFA Satellite: TNFA MAPK14 protein Q16539 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity 9606 BTO:0000887;BTO:0001103 15466486 NO lperfetto Here, we show that p38 activity facilitates myod and mef2 binding at a subset of late-activated promoters, and the binding of mef2d recruits pol ii. SIGNOR-129702 SIGNOR-ScTNFA Satellite: TNFA MAPK14 protein Q16539 UNIPROT ZFP36 protein P26651 UNIPROT down-regulates activity phosphorylation 10029 BTO:0005787 25815583 YES TTP appears to be a p38α/β MAPK target and pretreating skeletal muscle with a p38α/β MAPK inhibitor reduces TTP phosphorylation. SIGNOR-253596 SIGNOR-ScTNFA Satellite: TNFA MAPK14 protein Q16539 UNIPROT Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR up-regulates activity phosphorylation 10029 BTO:0005787 20887952 YES The chromatin redistribution of PRC2 in differentiating SCs is regulated by the p38a kinase, which promotes the formation of a complex containing p38a, EZH2, and YY1, via direct phosphorylation of EZH2. SIGNOR-253599 SIGNOR-ScTNFA Satellite: TNFA NFKBIA protein P25963 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 1340770 YES lperfetto Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b SIGNOR-217394 SIGNOR-ScTNFA Satellite: TNFA NFKBIA protein P25963 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 9914500 YES lperfetto In nonstimulated cells, nf-kappab is present in the cytosol where it is complexed to its inhibitor ikappab however, we found that only one of the activities, namely the ikk1/2 complex, exists as a pre-assembled kinase-substrate complex in which the ikks are directly or indirectly associated with several nf-kappab-related and ikappab-related proteins: rela, relb, crel, p100, p105, ikappa balpha, ikappa bbeta and ikappa bepsilon. SIGNOR-64092 SIGNOR-ScWNT Satellite: WNT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 22083140 YES lperfetto The role of apc is less clear, but it clearly binds to both b-catenin and axin, and could shuttle b-catenin from the plasma membrane and nucleus to the cytoplasmic axin complex. SIGNOR-227881 SIGNOR-ScWNT Satellite: WNT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates binding 9534 BTO:0000298 9482734 YES lperfetto Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin SIGNOR-227862 SIGNOR-ScWNT Satellite: WNT Wnt proteinfamily SIGNOR-PF40 SIGNOR Frizzled proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 9606 23290138 YES miannu Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-256173 SIGNOR-ScWNT Satellite: WNT Frizzled proteinfamily SIGNOR-PF11 SIGNOR DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 22944199 YES amattioni When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp. SIGNOR-253124 SIGNOR-ScWNT Satellite: WNT Frizzled proteinfamily SIGNOR-PF11 SIGNOR DVL1 protein O14640 UNIPROT up-regulates binding 19279717 YES apalma After binding of Wnt to the receptor complex, the signal is transduced to cytoplasmic phosphoprotein Dishevelled (Dsh/Dvl), and studies have uncovered that Dsh can directly interact with Fz SIGNOR-255892 SIGNOR-ScWNT Satellite: WNT RHOA protein P61586 UNIPROT ROCK1 protein Q13464 UNIPROT up-regulates activity binding 9606 25010901 YES gcesareni Rho-associated coiled-coil containing kinases (ROCK) were originally identified as effectors of the RhoA small GTPase SIGNOR-196740 SIGNOR-ScWNT Satellite: WNT RHOA protein P61586 UNIPROT ROCK1 protein Q13464 UNIPROT up-regulates activity binding 9606 23151663 YES gcesareni Planar cell polarity (pcp) signalling triggers activation of the small gtpases rhoa and rac1, which in turn activate rho kinase (rock) and jun-n-terminal kinase (jnk), respectively, leading to actin polymerization and microtubule stabilization. SIGNOR-199542 SIGNOR-ScWNT Satellite: WNT SDC4 protein P31431 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity binding 9606 BTO:0002314 BTO:0001103 23290138 YES apalma Rac1 is associated with Sdc4 and is activated by FN binding […] We observed that over-expression of Fzd7, or stimulation with FN resulted in increased levels of active Rac1 in primary myoblasts SIGNOR-255849 SIGNOR-ScWNT Satellite: WNT SDC4 protein P31431 UNIPROT FZD7/SDC4 complex SIGNOR-C216 SIGNOR form complex binding 9606 BTO:0002314 BTO:0001103 23290138 YES apalma We next examined whether endogenous Fzd7 and Sdc4 form a receptor complex in satellite cells […] Therefore, we conclude that Fzd7 and Sdc4 form a co-receptor complex in activated satellite cells. SIGNOR-255847 SIGNOR-ScWNT Satellite: WNT WNT7A protein O00755 UNIPROT FZD7 protein O75084 UNIPROT up-regulates activity binding 23290138 YES Simone Vumbaca Wnt7a-Fzd7 signaling stimulates symmetric stem cell divisions SIGNOR-255646 SIGNOR-ScWNT Satellite: WNT WNT7A protein O00755 UNIPROT FZD7 protein O75084 UNIPROT up-regulates activity binding 9606 BTO:0000887;BTO:0001103 22944199 YES gcesareni Analysis of the expression of the fzd receptors during somitogenesis demonstrated that fzd7 is expressed in the hypaxial region of the somite, suggesting an interaction with wnt7a. SIGNOR-198919 SIGNOR-ScWNT Satellite: WNT WNT7A protein O00755 UNIPROT FZD7 protein O75084 UNIPROT up-regulates activity binding 9606 BTO:0002314 BTO:0001103 23290138 YES apalma Our previous work has demonstrated that ligation of Wnt7a to Fzd7 activates the planar cell polarity (PCP) pathway […] Therefore, we conclude that the Fzd7/Sdc4 co-receptor complex binds both Wnt7a and FN. SIGNOR-255845 SIGNOR-ScWNT Satellite: WNT FN1 protein P02751 UNIPROT SDC4 protein P31431 UNIPROT up-regulates activity binding 9606 23290138 YES apalma Sdc4 is a high affinity receptor for fibronectin (FN) […] Therefore, we conclude that Sdc4 binds FN on activated satellite cells. SIGNOR-255846 SIGNOR-ScWNT Satellite: WNT DAAM1 protein Q9Y4D1 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity 9606 23151663 NO gcesareni In pcp, dvl binds to proteins such as pkc, atypical pkc (apkc), dvl?associated Activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58. SIGNOR-199381 SIGNOR-ScWNT Satellite: WNT DAAM1 protein Q9Y4D1 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity binding 9606 19365405 YES gcesareni B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1. SIGNOR-185268 SIGNOR-ScWNT Satellite: WNT FZD7 protein O75084 UNIPROT DVL1 protein O14640 UNIPROT up-regulates binding 22179044 YES apalma In non-canonical Wnt signalling, Wnt proteins bind Fzd and glypican-4, to activate Dsh at the cell membrane, leading to activation of Rho and JNK SIGNOR-255893 SIGNOR-ScWNT Satellite: WNT FZD7 protein O75084 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity 23290138 NO Simone Vumbaca We observed that overexpression of Fzd7 or stimulation with FN resulted in increased levels of active Rac1 in primary myoblasts SIGNOR-255647 SIGNOR-ScWNT Satellite: WNT FZD7 protein O75084 UNIPROT FZD7/SDC4 complex SIGNOR-C216 SIGNOR form complex binding 9606 BTO:0002314 BTO:0001103 23290138 YES apalma We next examined whether endogenous Fzd7 and Sdc4 form a receptor complex in satellite cells […] Therefore, we conclude that Fzd7 and Sdc4 form a co-receptor complex in activated satellite cells. SIGNOR-255848 SIGNOR-ScWNT Satellite: WNT ROCK1 protein Q13464 UNIPROT Satellite_cells_self-renewal phenotype SIGNOR-PH100 SIGNOR up-regulates transcriptional regulation BTO:0001103 23290138 NO apalma FN in the satellite cell niche is required for the maintenance of the overall satellite cell pool during muscle regeneration. Moreover, FN is necessary to potentiate Wnt7a signaling through the Fzd7/Scd4 receptor complex, which controls the regulation of satellite stem cell numbers SIGNOR-255850 SIGNOR-ScWNT Satellite: WNT CTNNB1 protein P35222 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 18316399 YES Simone Vumbaca Together, these results suggest that B-Cat increases MyoD binding to E box elements SIGNOR-255653 SIGNOR-ScWNT Satellite: WNT MYOD1 protein P15172 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 NO lperfetto The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop-helix (bHLH) motif that mediates dimerization and dna binding. [...] myogenic bHLH proteins form heterodimers with ubiquitous bHLH proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. SIGNOR-37458 SIGNOR-ScWNT Satellite: WNT DVL1 protein O14640 UNIPROT DAAM1 protein Q9Y4D1 UNIPROT up-regulates activity binding 9606 19365405 YES gcesareni B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1. SIGNOR-185271 SIGNOR-ScWNT Satellite: WNT DVL1 protein O14640 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity binding 9606 19365405 YES gcesareni B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1. SIGNOR-185274 SIGNOR-ScWNT Satellite: WNT DVL1 protein O14640 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity 9606 23151663 NO gcesareni In pcp , dvl binds to proteins such as pkc, atypical pkc (apkc), dvl associated activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58. SIGNOR-199384 SIGNOR-ScWNT Satellite: WNT DVL1 protein O14640 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9534 BTO:0004055 10196136 YES lperfetto We have recently found that Dvl-1 directly binds to Axin and that the binding of Dvl-1 to Axin does not affect the interaction of GSK-3beta with Axin. It is possible that the binding of Dvl to Axin induces the structural change of the Axin complex; therefore GSK-3beta does not effectively phosphorylate Axin. This is the first demostration showing that Dvl inhibits the function of GSK-3beta directly. SIGNOR-227917 SIGNOR-ScWNT Satellite: WNT DVL1 protein O14640 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9606 20837657 YES lperfetto In canonical wnt signaling, dsh phosphorylation inhibits the apcaxingsk3 complex, leading to beta-catenin stabilization. SIGNOR-227914 SIGNOR-ScWNT Satellite: WNT DVL1 protein O14640 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9606 20837657 YES lperfetto In canonical wnt signaling, dsh phosphorylation inhibits the apcaxingsk3 complex, leading to beta-catenin stabilization. SIGNOR-227911 SIGNOR-SDI Satellite: DDR inhibition DNA_damage stimulus SIGNOR-ST1 SIGNOR ATM protein Q13315 UNIPROT up-regulates activity 9606 BTO:0000007 12556884 NO miannu Cellular irradiation induces rapid intermolecular autophosphorylation of serine 1981 that causes dimer dissociation and initiates cellular ATM kinase activity. Most ATM molecules in the cell are rapidly phosphorylated on this site after doses of radiation as low as 0.5 Gy, and binding of a phosphospecific antibody is detectable after the introduction of only a few DNA double-strand breaks in the cell. Activation of the ATM kinase seems to be an initiating event in cellular responses to irradiation. SIGNOR-253376 SIGNOR-SDI Satellite: DDR inhibition DNA_damage stimulus SIGNOR-ST1 SIGNOR ATM protein Q13315 UNIPROT up-regulates 9606 21034966 NO lperfetto the ATM-Chk2 and ATR-Chk1 pathways, which are activated by DNA double-strand breaks (DSBs) and single-stranded DNA respectively. SIGNOR-242612 SIGNOR-SDI Satellite: DDR inhibition ATM protein Q13315 UNIPROT ABL1 protein P00519 UNIPROT up-regulates phosphorylation Ser446 PYPGIDLsQVYELLE 9606 BTO:0000938 9168116 YES lperfetto Ataxia telangiectasia mutant protein activates c-abl tyrosine kinase in response to ionizing radiation. Atm kinase domain corrects this defect, as it phosphorylates the c-abl tyrosine kinase in vitro at ser 465, leading to the activation of c-abl. SIGNOR-48818 SIGNOR-SDI Satellite: DDR inhibition ATM protein Q13315 UNIPROT ABL1 protein P00519 UNIPROT up-regulates binding 9606 9168117 YES acerquone Our results demonstrate that the sh3 domain of c-abl interacts with a dpapnpphfp motif (residues 1,373-1,382) of atm.These findings indicate that atm is involved in the activation of c-abl by dna damag SIGNOR-48822 SIGNOR-SDI Satellite: DDR inhibition ABL1 protein P00519 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates activity phosphorylation Tyr30 FATTDDFyDDPCFDSP 9606 BTO:0000007 12415271 YES We have found that c-Abl can phosphorylate MyoD at a conserved N-terminal tyrosine (Tyr30) that is located within the transactivation domain. Mutation of Tyr30 to Phe does not interfere with the function of MyoD, but theTyr30Phe mutant becomes resistant to the inhibitory effect of DNA damage. SIGNOR-253055 SIGNOR-SDI Satellite: DDR inhibition MYOD1 protein P15172 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 NO lperfetto The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop-helix (bHLH) motif that mediates dimerization and dna binding. [...] myogenic bHLH proteins form heterodimers with ubiquitous bHLH proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. SIGNOR-37458 SIGNOR-SM Satellite: Myostatin SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates activity binding 9606 12244043 YES areggio Taken together, these results suggest that myostatin inhibits MyoD activity and expression via Smad 3 resulting in the failure of the myoblasts to differentiate into myotubes SIGNOR-254986 SIGNOR-SM Satellite: Myostatin SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates activity transcriptional regulation 9606 12244043 NO areggio Taken together, these results suggest that myostatin inhibits MyoD activity and expression via Smad 3 resulting in the failure of the myoblasts to differentiate into myotubes SIGNOR-254987 SIGNOR-SM Satellite: Myostatin SMAD2 protein Q15796 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates activity binding 9606 phosphorylation:Ser465;Ser467 SPSVRCSsMS;SVRCSSMs 11274206 YES gcesareni the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4 SIGNOR-235183 SIGNOR-SM Satellite: Myostatin SMAD2 protein Q15796 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity binding 9606 9670020 YES lperfetto Smad2 and Smad3 form homo-oligomers upon phosphorylation by the constitutively active TGF-beta type I receptor, and this oligomerization does not require Smad4 SIGNOR-232149 SIGNOR-SM Satellite: Myostatin SMAD2 protein Q15796 UNIPROT SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR form complex binding 9606 phosphorylation:Ser465;Ser467 SPSVRCSsMS;SVRCSSMs 11274206 YES gcesareni the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4 SIGNOR-235188 SIGNOR-SM Satellite: Myostatin SMAD4 protein Q13485 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR form complex binding 9606 9843571 YES lperfetto TGF-beta treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. SIGNOR-229560 SIGNOR-SM Satellite: Myostatin SMAD4 protein Q13485 UNIPROT SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR form complex binding 9606 11274206 YES gcesareni the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4 SIGNOR-235178 SIGNOR-SM Satellite: Myostatin SMAD3 protein P84022 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates activity binding 10090 BTO:0000165 11711431 YES azuccotti We show that the TGF-beta intracellular effector Smad3, but not Smad2, mediates the inhibition of myogenic differentiation in MyoD-expressing C3H10T1/2 cells and C2C12 myoblasts by repressing the activity of the MyoD family of transcriptional factors. SIGNOR-252071 SIGNOR-SM Satellite: Myostatin SMAD3 protein P84022 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity binding 9534 9670020 YES lperfetto Smad2 and Smad3 form homo-oligomers upon phosphorylation by the constitutively active TGF-beta type I receptor, and this oligomerization does not require Smad4 SIGNOR-217227 SIGNOR-SM Satellite: Myostatin SMAD3 protein P84022 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates activity binding 9606 9843571 YES gcesareni TGF-² treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. SIGNOR-235168 SIGNOR-SM Satellite: Myostatin SMAD3 protein P84022 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR form complex binding 9606 9843571 YES lperfetto TGF-beta treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. SIGNOR-229557 SIGNOR-SM Satellite: Myostatin FST protein P19883 UNIPROT MSTN protein O14793 UNIPROT down-regulates activity binding 10090 24627466 YES lperfetto Follistatin (FST) is a member of the tissue growth factor beta family and is a secreted glycoprotein that antagonizes many members of the family, including activin A, growth differentiation factor 11, and myostatin. FST315-deltaHBS-Fc induced improvements in muscle repair after injury/atrophy by modulating the early inflammatory phase allowing for increased macrophage density, and Pax7-positive cells leading to an accelerated restoration of myofibers and muscle function. SIGNOR-251717 SIGNOR-SM Satellite: Myostatin FST protein P19883 UNIPROT MSTN protein O14793 UNIPROT down-regulates activity binding 10090 11459935 YES gcesareni Binding of myostatin to Act RIIB could be inhibited by the activin-binding protein follistatin and, at higher concentrations, by the myostatin propeptide. T SIGNOR-235150 SIGNOR-SM Satellite: Myostatin MSTN protein O14793 UNIPROT ACVR2B protein Q13705 UNIPROT up-regulates activity binding 10090 11459935 YES gcesareni The purified C-terminal myostatin dimer was capable of binding the activin type II receptors, Act RIIB and, to a lesser extent, Act RIIA SIGNOR-235153 SIGNOR-SM Satellite: Myostatin ACVR2B protein Q13705 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation 10090 21966641 YES areggio It has been suggested that binding of myostatin to the ActRIIB results in the phosphorylation of two serine residues of Smad2 or Smad3 at COOH domains SIGNOR-254985 SIGNOR-SM Satellite: Myostatin ACVR2B protein Q13705 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation 10090 21966641 YES areggio It has been suggested that binding of myostatin to the ActRIIB results in the phosphorylation of two serine residues of Smad2 or Smad3 at COOH domains SIGNOR-254984 SIGNOR-SM Satellite: Myostatin MYOD1 protein P15172 UNIPROT FST protein P19883 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 15130492 NO lperfetto MyoD, CREB, and NFAT Mediate the Transcriptional Activation of the Follistatin Promoter Induced by TSA SIGNOR-251727 SIGNOR-SM Satellite: Myostatin MYOD1 protein P15172 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 NO lperfetto The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop-helix (bHLH) motif that mediates dimerization and dna binding. [...] myogenic bHLH proteins form heterodimers with ubiquitous bHLH proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. SIGNOR-37458 SIGNOR-SMN Satellite: miRNA network NfKb-p65/p50 complex SIGNOR-C13 SIGNOR miR-155 mirna URS000062749E_9606 RNAcentral up-regulates quantity by expression transcriptional regulation 10090 18619954 NO We found that directed expression of MRFs in the neural tube of chicken embryos induced ectopic expression of miR-1 and miR-206. Conversely, the lack of Myf5 but not of MyoD resulted in a loss of miR-1 and miR-206 expression. SIGNOR-255920 SIGNOR-SMN Satellite: miRNA network PIP3 smallmolecule CHEBI:16618 ChEBI AKT1 protein P31749 UNIPROT up-regulates activity relocalization 9606 21798082 YES lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositidedependent kinase 1 pdk1) and akt, and the subsequent phosphorylation of akt at serine 308 by pdk1, leading to akt activation. SIGNOR-236349 SIGNOR-SMN Satellite: miRNA network PIP3 smallmolecule CHEBI:16618 ChEBI AKT1 protein P31749 UNIPROT up-regulates activity relocalization 9606 23633519 YES lperfetto Akt is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates pips) with phosphate groups at positions 3,4 and 3,4,5 on the inositol ring. SIGNOR-252641 SIGNOR-SMN Satellite: miRNA network PIP3 smallmolecule CHEBI:16618 ChEBI AKT1 protein P31749 UNIPROT up-regulates activity relocalization 9606 23119004 YES lperfetto Binding of igf to igf-ir activates pi3k to generate pip3 which in turn recruits and activates proteins that contain a pleckstrin homology ph) domain, including akt and pdk1. SIGNOR-252642 SIGNOR-SMN Satellite: miRNA network PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 YES lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 SIGNOR-SMN Satellite: miRNA network PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation -1 9094314 YES gcesareni We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1) SIGNOR-243274 SIGNOR-SMN Satellite: miRNA network miR-4784 mirna URS000021E7E5_9606 RNAcentral AHDC1 protein Q5TGY3 UNIPROT up-regulates quantity by expression 10090 19933931 YES The activation state of the IGF-1 signal transduction cascade reciprocally regulates miR-1 expression through the Foxo3a transcription factor; SIGNOR-255720 SIGNOR-SMN Satellite: miRNA network miR-155 mirna URS000062749E_9606 RNAcentral SPI1 protein P17947 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 22195016 YES Our results elucidate a negative feedback circuit in which IGF-1-stimulated miR-133 in turn represses IGF-1R expression to modulate the IGF-1R signaling pathway during skeletal myogenesis. SIGNOR-255915 SIGNOR-SMN Satellite: miRNA network miR-155 mirna URS000062749E_9606 RNAcentral MYC protein P01106 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 19933931 YES On the basis of bioinformatics tools, biochemical assays, and in vivo models, we demonstrate that (1) insulin-like growth factor-1 (IGF-1) and IGF-1 receptor are targets of miR-1 SIGNOR-255721 SIGNOR-SMN Satellite: miRNA network mir-206 mirna URS0000389B41_9606 RNAcentral PAX7 protein P23759 UNIPROT down-regulates quantity post transcriptional regulation 10090 20819939 YES We show that miR-1 and miR-206 facilitate satellite cell differentiation by restricting their proliferative potential. We identify Pax7 as one of the direct regulatory targets of miR-1 and miR-206. Inhibition of miR-1 and miR-206 substantially enhances satellite cell proliferation and increases Pax7 protein level in vivo SIGNOR-255921 SIGNOR-SMN Satellite: miRNA network miR221 mirna URS0000245997_9606 RNAcentral MEOX2 protein P50222 UNIPROT down-regulates quantity 10090 20819939 YES We show that miR-1 and miR-206 facilitate satellite cell differentiation by restricting their proliferative potential. We identify Pax7 as one of the direct regulatory targets of miR-1 and miR-206. Inhibition of miR-1 and miR-206 substantially enhances satellite cell proliferation and increases Pax7 protein level in vivo SIGNOR-255922 SIGNOR-SMN Satellite: miRNA network miR221 mirna URS0000245997_9606 RNAcentral ZEB2 protein O60315 UNIPROT down-regulates quantity by repression destabilization 10090 26762731 YES We identified miR-143 as a regulator of the insulin growth factor-binding protein 5 (Igfbp5) in primary myoblasts and show that the expression of miR-143 and its target gene is disrupted in satellite cells from old mice. SIGNOR-255939 SIGNOR-SMN Satellite: miRNA network ZBTB16 protein Q05516 UNIPROT miR-146a mirna URS000075D8A0_9606 RNAcentral down-regulates quantity by repression transcriptional regulation 9606 22327366 YES In endothelial cells. KLF2 binds to the promoter and induces a signi cant upregulation of the miR-143/145 cluster SIGNOR-255941 SIGNOR-SMN Satellite: miRNA network PAX7 protein P23759 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates quantity by destabilization 10090 17548510 NO Simone Vumbaca Previously, we showed that Pax7 overexpression in adult primary myoblasts down-regulates MyoD and prevents myogenin induction, inhibiting myogenesis. We show that Pax7 prevents muscle differentiation independently of its transcriptional activity, affecting MyoD function. [...] Pax7 expression affects MyoD protein stability SIGNOR-255637 SIGNOR-SMN Satellite: miRNA network PIK3CA protein P42336 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24367090 YES AKT is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates (PIPs) with phosphate s at positions 3, 4 and 3,4,5 on the inositol ring miannu Insulin activation of phosphoinositide 3-kinase (pi3k) signaling regulates glucose homeostasis through the production of phosphatidylinositol 3,4,5-trisphosphate (pip3). The dual-specificity phosphatase and tensin homolog deleted on chromosome 10 (pten) blocks pi3k signaling by dephosphorylating pip3, and is inhibited through its interaction with phosphatidylinositol 3,4,5-trisphosphate-dependent rac exchanger 2 SIGNOR-147948 SIGNOR-SMN Satellite: miRNA network PIK3CA protein P42336 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 YES AKT is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates (PIPs) with phosphate s at positions 3, 4 and 3,4,5 on the inositol ring miannu Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, which recruit akt to the plasma membrane through its pleckstrin homology (ph) domain, permitting its activation by pdks. SIGNOR-65409 SIGNOR-SMN Satellite: miRNA network MYOG protein P15173 UNIPROT mir-133a2 mirna URS00005675D3_9606 RNAcentral up-regulates quantity transcriptional regulation 10090 18619954 NO We found that directed expression of MRFs in the neural tube of chicken embryos induced ectopic expression of miR-1 and miR-206. Conversely, the lack of Myf5 but not of MyoD resulted in a loss of miR-1 and miR-206 expression. SIGNOR-255919 SIGNOR-SMN Satellite: miRNA network MYOG protein P15173 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0001103 28163303 NO apalma During early stages of myogenesis, CIITA binds directly to myogenin (MYOG) and inactivates it, preventing MYOG-mediated induction of myogenic genes that are required for muscle differentiation and function SIGNOR-255112 SIGNOR-SMN Satellite: miRNA network MYOG protein P15173 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates activity BTO:0001103 7532173 NO Simone Vumbaca These results suggest that at least initially, the muscle-forming regions contained cells with myogenic potential, and that this potential is lost in the myogenin mutants as development proceeds. SIGNOR-255644 SIGNOR-SMN Satellite: miRNA network MYOG protein P15173 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0000887 8288123 NO lperfetto The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop--helix (bhlh) motif that mediates dimerization and dna binding. / myogenic bhlh proteins form heterodimers with ubiquitous bhlh proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enancers. SIGNOR-37461 SIGNOR-SMN Satellite: miRNA network IRS1 protein P35568 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates activity binding 9606 20966354 YES lperfetto Irs proteins are capable of both regulating and activating pi3k, depending on the cell of origin. SIGNOR-168985 SIGNOR-SMN Satellite: miRNA network PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Thr308 KDGATMKtFCGTPEY 9606 21798082 YES gcesareni Pip3 acts in turn as a docking site for two kinases, phosphoinositidedependent kinase 1 (pdk1) and akt, and the subsequent phosphorylation of akt at serine 308 by pdk1, leading to akt activation. SIGNOR-175675 SIGNOR-SMN Satellite: miRNA network PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 19951971 YES lperfetto PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain. SIGNOR-249629 SIGNOR-SMN Satellite: miRNA network MYC protein P01106 UNIPROT miR-23b mirna URS0000283D0A_9606 RNAcentral down-regulates quantity by repression transcriptional regulation 10090 16731620 YES Moreover, both loci encoding miR-1, miR-1-1, and miR-1-2, and two of the three encoding miR-133, miR-133a-1 and miR-133a-2, are strongly induced during myogenesis.[…]By using CHIP analysis, we demonstrate that the myogenic factors Myogenin and MyoD bind to regions upstream of these microRNAs and, therefore, are likely to regulate their expression. SIGNOR-255916 SIGNOR-SMN Satellite: miRNA network IGFBP5 protein P24593 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates activity 10090 BTO:0000165 18762576 NO These findings suggest that IGFBP-5 promotes muscle cell differentiation by binding to and switching on the IGF-II auto-regulation loop. SIGNOR-255940 SIGNOR-SMN Satellite: miRNA network AKT1 protein P31749 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates activity 9606 BTO:0000222 BTO:0000887;BTO:0001103 10896679 NO lperfetto Two candidates that may function as mediators of pi3-k in the phosphorylation of mef2 proteins are pkb and big map kinase 1. SIGNOR-79335 SIGNOR-SMN Satellite: miRNA network AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249626 SIGNOR-SMN Satellite: miRNA network AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249627 SIGNOR-SMN Satellite: miRNA network AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249625 SIGNOR-SMN Satellite: miRNA network FOXO3 protein O43524 UNIPROT DIO2 protein Q92813 UNIPROT up-regulates quantity by expression transcriptional regulation 20978344 NO Forkhead box O3 (FoxO3) was identified as a key molecule inducing D2 expression and thereby increasing intracellular T3 production. Accordingly, FoxO3-depleted primary myoblasts also had a differentiation deficit that could be rescued by high levels of T3. SIGNOR-256204 SIGNOR-SMN Satellite: miRNA network DIO2 protein Q92813 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20978344 NO miannu The active thyroid hormone 3,5,3' triiodothyronine (T3) is a major regulator of skeletal muscle function. The deiodinase family of enzymes controls the tissue-specific activation and inactivation of the prohormone thyroxine (T4). Here we show that type 2 deiodinase (D2) is essential for normal mouse myogenesis and muscle regeneration. Indeed, D2-mediated increases in T3 were essential for the enhanced transcription of myogenic differentiation 1 (MyoD) and for execution of the myogenic program. SIGNOR-256203 SIGNOR-SMN Satellite: miRNA network MEF2C protein Q06413 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 9606 9418854 YES lperfetto Myod-e protein heterodimers interact with mef2 proteins to synergistically activate myogenesis. SIGNOR-54089 SIGNOR-SMN Satellite: miRNA network MYOD1 protein P15172 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001103 15870273 YES Simone Vumbaca We suggest that the interaction between MyoD and Pbx is necessary to initially target MyoD to the myogenin promoter SIGNOR-255639 SIGNOR-SMN Satellite: miRNA network MYOD1 protein P15172 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001103 12694204 YES Simone Vumbaca We conclude that MyoD is the major MRF that binds to the E-box from the myogenin promoter during differentiation. SIGNOR-255640 SIGNOR-SMN Satellite: miRNA network MYOD1 protein P15172 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 NO lperfetto The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop-helix (bHLH) motif that mediates dimerization and dna binding. [...] myogenic bHLH proteins form heterodimers with ubiquitous bHLH proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. SIGNOR-37458 SIGNOR-SMN Satellite: miRNA network MYF5 protein P13349 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 NO miannu The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop--helix (bhlh) motif that mediates dimerization and dna binding. / myogenic bhlh proteins form heterodimers with ubiquitous bhlh proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. SIGNOR-37409 SIGNOR-SMN Satellite: miRNA network IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr1179 GLENGLNyIDLDLVK 9606 17827393 YES gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). SIGNOR-157730 SIGNOR-SMN Satellite: miRNA network IGF1 protein P05019 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity binding 9606 21798082 YES lperfetto Binding of IGF1 to its receptor leads to activation of its intrinsic tyrosine kinase and autophosphorylation, thus generating docking sites for insulin receptor substrate (IRS), which is also phosphorylated by the IGF1 receptor. SIGNOR-175662 SIGNOR-SMN Satellite: miRNA network IGF1 protein P05019 UNIPROT IGF1R protein P08069 UNIPROT up-regulates binding 9606 19029956 YES lperfetto At the cellular level, the ligands IGF1, IGF2 and insulin bind to various members of the insulin receptor (IR) - IGF1 receptor (IGF1R) family. SIGNOR-182484 SIGNOR-SPAM Satellite: Prostaglandins and myogenesis acetylsalicylic acid chemical CHEBI:15365 ChEBI PTGS2 protein P35354 UNIPROT down-regulates chemical inhibition 9606 11809688 YES gcesareni Nsaids inhibit cyclooxygenase (cox) isozymes, which are responsible for the committed step in prostaglandin biosynthesis, and this has been considered the primary mechanism by which nsaids exert their antitumorigenic effects. SIGNOR-114380 SIGNOR-SPAM Satellite: Prostaglandins and myogenesis arachidonic acid smallmolecule CHEBI:15843 ChEBI PTGS2 protein P35354 UNIPROT up-regulates 9606 15878913 NO miannu AA increases PC-3 prostate tumor cell growth, total DNA content and endogenous PGE 2 levels via induction of c-fos , cPLA 2 and cox-2 mRNA transcription. SIGNOR-255394 SIGNOR-SPAM Satellite: Prostaglandins and myogenesis prostaglandin F2alpha smallmolecule CHEBI:15553 ChEBI Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 9606 20219869 NO apalma Prostaglandins are able to affect muscle cell proliferation (142), differentiation (96) and fusion (141), and can also modulate muscle fiber growth and the synthesis and degradation of proteins in muscle SIGNOR-256213 SIGNOR-SPAM Satellite: Prostaglandins and myogenesis prostaglandin F2alpha smallmolecule CHEBI:15553 ChEBI Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 20219869 NO apalma Prostaglandins are able to affect muscle cell proliferation (142), differentiation (96) and fusion (141), and can also modulate muscle fiber growth and the synthesis and degradation of proteins in muscle SIGNOR-255360 SIGNOR-SPAM Satellite: Prostaglandins and myogenesis prostaglandin F2alpha smallmolecule CHEBI:15553 ChEBI Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 3308494 NO apalma The results suggest a role for prostanoids in the regulation of both human myoblast proliferation and differentiation SIGNOR-255362 SIGNOR-SPAM Satellite: Prostaglandins and myogenesis PTGS2 protein P35354 UNIPROT IL4 protein P05112 UNIPROT up-regulates 9606 22225874 YES FFerrentino Cox2 Is a Direct Srf Target Gene and Controls Il4 Expression SIGNOR-255967 SIGNOR-SPAM Satellite: Prostaglandins and myogenesis PTGS2 protein P35354 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0001103 20219869 YES apalma Furthermore, COX-2 inhibition reduced MyoD expression in regenerating muscle, suggesting a role for COX-2 in modulating muscle differentiation, as well as growth SIGNOR-256214 SIGNOR-SPAM Satellite: Prostaglandins and myogenesis PTGS2 protein P35354 UNIPROT prostaglandin F2alpha smallmolecule CHEBI:15553 ChEBI up-regulates chemical modification 9606 11751058 YES gcesareni Cox catalyzes two enzymatic activities;namely, the conversion of aa to the hydroperoxy endoperoxide pgg2, followed by its subsequent reduction to the labile product pgh2. Pgh2_ is the common substrate for a number of different cell-specific synthases, which convert pgh2_ to the individual pgs or tx, including pge2, pgi2_ (prostacyclin), pgd2, pgf2alfa, and txa2. SIGNOR-113291 SIGNOR-SPAM Satellite: Prostaglandins and myogenesis SRF protein P11831 UNIPROT IL6 protein P05231 UNIPROT up-regulates 9606 22225874 YES FFerrentino Srf within myofibers modulates Il6 and Cox2/Il4 expressions and, therefore, exerts a paracrine control of satellite cell proliferation and fusion, respectively, which in turn support skeletal muscle hypertrophy. SIGNOR-255966 SIGNOR-SPAM Satellite: Prostaglandins and myogenesis SRF protein P11831 UNIPROT PTGS2 protein P35354 UNIPROT up-regulates 9606 22225874 YES FFerrentino Srf within myofibers modulates Il6 and Cox2/Il4 expressions and, therefore, exerts a paracrine control of satellite cell proliferation and fusion, respectively, which in turn support skeletal muscle hypertrophy. SIGNOR-255965 SIGNOR-SPAM Satellite: Prostaglandins and myogenesis MYOD1 protein P15172 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 NO lperfetto The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop-helix (bHLH) motif that mediates dimerization and dna binding. [...] myogenic bHLH proteins form heterodimers with ubiquitous bHLH proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. SIGNOR-37458 SIGNOR-SPAM Satellite: Prostaglandins and myogenesis IL4 protein P05112 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 10090 12757709 NO miannu These data demonstrate that following myotube formation, myotubes recruit myoblast fusion by secretion of IL-4, leading to muscle growth SIGNOR-255896 SIGNOR-TLymphATP T-Lymphocyte: ATP ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR T-reg_differentiation phenotype SIGNOR-PH91 SIGNOR down-regulates 9606 23620016 NO In the current study, addition of ERK inhibitors suppressed IL-6-induced RORgammat expression and promoted TGF-beta-induced Foxp3 expression. SIGNOR-254686 SIGNOR-TLymphATP T-Lymphocyte: ATP ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR T-reg_differentiation phenotype SIGNOR-PH91 SIGNOR down-regulates 9606 21364186 NO Lowering the extent of costimulation of P2X in T cells diminishes the extent of ERK phosphorylation without affecting TCR-mediated nuclear translocation of NFAT (10). In Tregs, this mechanism would favor the stability of their transcriptional program through the stabilization of nuclear complexes of NFAT and Foxp3 (47). SIGNOR-254687 SIGNOR-TLymphATP T-Lymphocyte: ATP FOXP3 protein Q9BZS1 UNIPROT T-reg_differentiation phenotype SIGNOR-PH91 SIGNOR up-regulates 9606 15785758 NO mrosina Viewed as a whole, the available data demonstrate essential involvement of Foxp3 in the development and function of CD4 + CD25 + T reg cells. SIGNOR-254970 SIGNOR-TLymphATP T-Lymphocyte: ATP PLD2 protein O14939 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 18423386 NO mrosina Altogether, these data suggest that PLD acting upstream of the MAP kinases ERK1/2 may play a key role in the regulation of IL-2 production by stimulated Jurkat cells. SIGNOR-254983 SIGNOR-TLymphATP T-Lymphocyte: ATP P2RX7 protein Q99572 UNIPROT PLD2 protein O14939 UNIPROT up-regulates 9606 8573088 NO mrosina This study shows that extracellular ATP, acting through the P2Z purinoceptor, stimulated PLD activity in human lymphocytes. SIGNOR-254966 SIGNOR-TLymphIFNG T-Lymphocyte: IFN gamma IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR STAT1 protein P42224 UNIPROT up-regulates activity binding 9606 23898330 YES lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249494 SIGNOR-TLymphIFNG T-Lymphocyte: IFN gamma IFNG protein P01579 UNIPROT IFNGR2 protein P38484 UNIPROT up-regulates binding 9606 7673114 YES gcesareni Ifn-g Binds to the ifn-g Receptor binding subunit (ifn-gR1;receptor chain 1), a species-specific cell surface transmembrane receptor chain (41, 42). A second transmembrane protein (ifn-gR2) (43 45) is required for signal transduction SIGNOR-31013 SIGNOR-TLymphIFNG T-Lymphocyte: IFN gamma IFNG protein P01579 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates activity binding 9606 BTO:0000801 23898330 YES lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249484 SIGNOR-TLymphIFNG T-Lymphocyte: IFN gamma IFNG protein P01579 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates binding 9606 10986460 YES fspada Molecular interactions among cytokines and cytokine receptors form the basis of many cell-signaling pathways relevant to immune function. Interferon-g (ifng) signals through a multimeric receptor complex consistingof two different but structurally related transmembrane chains: the high-affinityreceptor-binding subunit (ifn-gra) and a species-specific accessory factor (af-1 or ifn-grb). SIGNOR-81804 SIGNOR-TLymphIFNG T-Lymphocyte: IFN gamma IFNG protein P01579 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates binding 9606 12438563 YES gcesareni Ifn-g Binds to the ifn-g Receptor binding subunit (ifn-gR1;receptor chain 1), a species-specific cell surface transmembrane receptor chain (41, 42). A second transmembrane protein (ifn-gR2) (4345) is required for signal transduction SIGNOR-95626 SIGNOR-TLymphIFNG T-Lymphocyte: IFN gamma IFNG protein P01579 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR up-regulates activity binding 9606 BTO:0000801 23898330 YES lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249487 SIGNOR-TLymphIFNG T-Lymphocyte: IFN gamma PROX1 protein Q92786 UNIPROT RORC protein P51449 UNIPROT down-regulates 23723244 NO azuccotti In this study, we identify Prospero-related homeobox 1 (Prox1) as a novel co-repressor of the retinoic acid-related orphan receptors, RORgamma and RORalpha. Prox1 interacts directly with RORgamma and RORalpha and negatively regulates their transcriptional activity. SIGNOR-254507 SIGNOR-TLymphIFNG T-Lymphocyte: IFN gamma PROX1 protein Q92786 UNIPROT IFNG protein P01579 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20064070 NO Human PROX1 is involved in biologic functions closely tied to HIV infection, most notably as a negative regulator of interferon (IFN) gamma expression in T cells SIGNOR-254506 SIGNOR-TLymphIFNG T-Lymphocyte: IFN gamma IFNGR1 protein P15260 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 17063185 YES flangone Interferon- (ifn;type ii ifn) induces reorganization of the ifn-receptor subunits, ifngr1 and ifngr2, activating the janus kinases jak1 and jak2, which are constitutively associated with each subunit, respectively SIGNOR-150194 SIGNOR-TLymphIFNG T-Lymphocyte: IFN gamma IFNGR1 protein P15260 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 15864272 YES gcesareni The only type ii ifn, ifn-g, binds a distinct cell-surface receptor, which is known as the type ii ifn receptor. This receptor is also composed of two subunits, ifngr1 and ifngr2, which are associated with jak1 and jak2, respectively. Activation of the jaks that are associated with the type i ifn receptor results in tyrosine phosphorylation of stat2 SIGNOR-135952 SIGNOR-TLymphIFNG T-Lymphocyte: IFN gamma IFNGR1 protein P15260 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR form complex binding 9606 BTO:0000801 19041276 YES lperfetto The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process. SIGNOR-249485 SIGNOR-TLymphIFNG T-Lymphocyte: IFN gamma GATA3 protein P23771 UNIPROT TBX21 protein Q9UL17 UNIPROT down-regulates 9606 16386358 NO Conversely, T-bet is capable of inhibiting GATA-3 (Szabo et al., 2000). The mutual inhibition between GATA-3 and T-bet ensures that Th1 and Th2 cells express one or the other molecule (T-bet in Th1, and GATA-3 in Th2), but not both SIGNOR-254296 SIGNOR-TLymphIFNG T-Lymphocyte: IFN gamma GATA3 protein P23771 UNIPROT GATA3 protein P23771 UNIPROT up-regulates 9606 16386358 YES Experimental data indeed supports the existence of a positive circuit involvingGATA-3 that excludes IL-4 and STAT-6, specifically in mouse cells SIGNOR-254297 SIGNOR-TLymphIFNG T-Lymphocyte: IFN gamma STAT1 protein P42224 UNIPROT TBX21 protein Q9UL17 UNIPROT up-regulates 9606 16386358 NO T-bet is a transcription factor detected in Th1, but not in Th0 or Th2 cells. Its expression is up-regulated by IFN-gamma, through a STAT-1-dependent mechanism SIGNOR-254293 SIGNOR-TLymphIFNG T-Lymphocyte: IFN gamma STAT1 protein P42224 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity binding 9606 19041276 YES lperfetto Each STAT1 monomer becomes tyrosine phosphorylated at tyrosine 701 by the JAKs, dissociates from the receptor to form a STAT1-STAT1 homodimer which translocates to the nucleus SIGNOR-249495 SIGNOR-TLymphIFNG T-Lymphocyte: IFN gamma IFNGR2 protein P38484 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR form complex binding 9606 BTO:0000801 19041276 YES lperfetto The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process. SIGNOR-249486 SIGNOR-TLymphIFNG T-Lymphocyte: IFN gamma TBX21 protein Q9UL17 UNIPROT TBX21 protein Q9UL17 UNIPROT up-regulates 9606 16386358 YES In turn, T-bet is an IFN-gamma activator (Szabo et al., 2000), thus creating an indirect positive feedback. Furthermore, it has been shown that ectopic T-bet is able to induce the transcription of its own gene SIGNOR-254294 SIGNOR-TLymphIFNG T-Lymphocyte: IFN gamma TBX21 protein Q9UL17 UNIPROT GATA3 protein P23771 UNIPROT down-regulates 9606 16386358 NO Conversely, T-bet is capable of inhibiting GATA-3 (Szabo et al., 2000). The mutual inhibition between GATA-3 and T-bet ensures that Th1 and Th2 cells express one or the other molecule (T-bet in Th1, and GATA-3 in Th2), but not both SIGNOR-254295 SIGNOR-TLymphIFNG T-Lymphocyte: IFN gamma TBX21 protein Q9UL17 UNIPROT IFNG protein P01579 UNIPROT up-regulates quantity by expression transcriptional regulation 17541280 NO T-bet is crucially implicated in Th1 differentiation due to its strong promoting activity for IFN-gamma gene transcription SIGNOR-254508 SIGNOR-TLymphIFNG T-Lymphocyte: IFN gamma JAK1 protein P23458 UNIPROT IFNGR2 protein P38484 UNIPROT up-regulates activity phosphorylation 9606 19041276 YES lperfetto The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process. SIGNOR-249491 SIGNOR-TLymphIFNG T-Lymphocyte: IFN gamma JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS -1 7657660 YES lperfetto Stat1 was phosphorylated at tyr 701 in jak immune complex kinase reaction. The stat1 and stat2 proteins are present in the cytoplasm of untreated cells;upon stimulation with ifn-g, They become rapidly activated by tyrosine phosphorylation at a single site catalyzed by receptor associated jak (janus) kinases. SIGNOR-30905 SIGNOR-TLymphIFNG T-Lymphocyte: IFN gamma JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 9020188 YES lperfetto The stat1 and stat2 proteins are present in the cytoplasm of untreated cells;upon stimulation with ifn-g they become rapidly activated by tyrosine phosphorylation at a single site catalyzed by receptor associated jak (janus) kinases. SIGNOR-236239 SIGNOR-TLymphIFNG T-Lymphocyte: IFN gamma JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000567 11823427 YES lperfetto The central event in cytokine_dependent transcriptional regulation is phosphorylation of STATs on a single tyrosine residue at their C_terminus (Darnell, 1997b). The reaction is catalyzed by cytokine receptor_associated tyrosine kinases of the Janus type (Jak) at the cell membrane and triggers the homo_ and heterodimerization of STAT molecules via reciprocal phosphotyrosine“SH2 domain interactions SIGNOR-236373 SIGNOR-TLymphIFNG T-Lymphocyte: IFN gamma JAK1 protein P23458 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 19041276 YES lperfetto The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process. SIGNOR-249488 SIGNOR-TLymphIFNG T-Lymphocyte: IFN gamma JAK1 protein P23458 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates phosphorylation Tyr457 KAPTSFGyDKPHVLV 9606 7615558 YES lperfetto Interferon gamma activation of stat1alpha requires both jak1 and jak2 as well as tyrosine phosphorylation of the alpha chain of the ifngamma receptor. SIGNOR-29866 SIGNOR-TLymphIFNG T-Lymphocyte: IFN gamma JAK1 protein P23458 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000801 19041276 YES lperfetto The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process. SIGNOR-249492 SIGNOR-TLymphIL10 T-Lymphocyte: IL10 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr637 KFGSLDTyLKKNKNC 9606 BTO:0000007 19364823 YES 16705160:The effect of Ser523 on Jak2 function was independent of Tyr570-mediated inhibition. lperfetto Analysis of in vitro autophosphorylated jak2while cytokine receptor stimulation mediates the phosphorylation of both tyr317 and tyr637, these residues oppositely regulate jak2-dependent signaling: the mutation of tyr317 enhances jak2 function, suggesting a role for the phosphorylation of tyr317 in the inhibition of jak2. Conversely, mutation of tyr637 reduces jak2 signaling, suggesting a role for the phosphorylation of this residue in the activation of jak2. SIGNOR-235885 SIGNOR-TLymphIL10 T-Lymphocyte: IL10 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1007 VLPQDKEyYKVKEPG -1 9111318 YES Multiple autophosphorylation sites on Jak2, including Y1007 and Y1008. Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop. SIGNOR-251357 SIGNOR-TLymphIL10 T-Lymphocyte: IL10 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr221 IRAKIQDyHILTRKR 9606 BTO:0000007 15143187 YES JAK2 is autophosphorylated on tyrosines 221 and 1007. tyrosines 221 and 570 in JAK2 may serve as regulatory sites in JAK2, with phosphorylation of tyrosine 221 increasing kinase activity and phosphorylation of tyrosine 570 decreasing kinase activity SIGNOR-251356 SIGNOR-TLymphIL10 T-Lymphocyte: IL10 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT unknown phosphorylation Tyr1007 VLPQDKEyYKVKEPG -1 9111318 YES Within the Jak2 kinase domain, there is a region that has considerable sequence homology to the regulatory region of the insulin receptor and contains two tyrosines, Y1007 and Y1008, that are potential regulatory sites. Y1007 and Y1008 are sites of trans- or autophosphorylation in vivo and in in vitro kinase reactions. Mutation of Y1007, or both Y1007 and Y1008, to phenylalanine essentially eliminated kinase activity, whereas mutation of Y1008 to phenylalanine had no detectable effect on kinase activity SIGNOR-251358 SIGNOR-TLymphIL10 T-Lymphocyte: IL10 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity phosphorylation Tyr570 VRREVGDyGQLHETE 9606 BTO:0000007 15143187 YES JAK2 is autophosphorylated on tyrosines 221 and 1007. tyrosines 221 and 570 in JAK2 may serve as regulatory sites in JAK2, with phosphorylation of tyrosine 221 increasing kinase activity and phosphorylation of tyrosine 570 decreasing kinase activity SIGNOR-251359 SIGNOR-TLymphIL10 T-Lymphocyte: IL10 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr201 DQTPLAIyNSISYKT 9534 BTO:0000298 17027227 YES Site of Jak2 tyrosine autophosphorylation; namely, tyrosine 201. Jak2 tyrosine residue 201 was the principal mediator of SHP-2 binding as conversion of this tyrosine residue to phenylalanine abolished this interaction SIGNOR-251360 SIGNOR-TLymphIL10 T-Lymphocyte: IL10 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr972 EYLGTKRyIHRDLAT 9606 BTO:0000007 20304997 YES lperfetto Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity SIGNOR-236294 SIGNOR-TLymphIL10 T-Lymphocyte: IL10 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr813 NSLFTPDyELLTEND 9606 BTO:0000007 15121872 YES 16705160:The effect of Ser523 on Jak2 function was independent of Tyr570-mediated inhibition. lperfetto Tyrosine 813 is a site of jak2 autophosphorylation critical for activation of jak2 by sh2-b betawe show that phosphorylation of tyrosine 813 is required for the sh2 domain-containing adapter protein sh2-b beta to bind jak2 and to enhance the activity of jak2 and stat5b. SIGNOR-235910 SIGNOR-TLymphIL10 T-Lymphocyte: IL10 FOXP3 protein Q9BZS1 UNIPROT IL10 protein P22301 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 24315995 NO alessandro FoxP3, a lineage-specification factor, executes its multiple activities mostly through transcriptional regulation of target genes. We identified an interleukin-10 (IL-10)-producing FoxP3(+) T regulatory cell population that contributes to IL-10-dependent type 2 cytokine bias in breast-cancer patients. Although genetic ablation of FOXP3 inhibited IL10 transcription, genome-wide analysis ruled out its role as a transcription factor for IL10 SIGNOR-254525 SIGNOR-TLymphIL10 T-Lymphocyte: IL10 IL10 protein P22301 UNIPROT IL10RA protein Q13651 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0000776 10347215 YES milica Functionally active il-10 receptors are composed of two distinct subunits. The il-10 receptor ? Chain is a 110-kda polypeptide that plays the dominant role in mediating high affinity ligand binding and signal transduction. The il-10 receptor ? Subunit (also known as crf2_4) is predicted to be a 40-kda polypeptide that is largely required only for signaling SIGNOR-67964 SIGNOR-TLymphIL10 T-Lymphocyte: IL10 IL10 protein P22301 UNIPROT IL10RA protein Q13651 UNIPROT up-regulates activity binding 9606 BTO:0000801 26260587 YES lperfetto IL10 is a classic anti-inflammatory cytokine and its molecular signalling pathway has been well characterized in macrophages and T lymphocytes. Secreted IL10 cytokine binds to the IL10 receptor 1 (IL10R1) on membrane surfaces, and IL10R1 dimerizes with IL10R2 to exert its downstream effects. SIGNOR-249544 SIGNOR-TLymphIL10 T-Lymphocyte: IL10 TBX21 protein Q9UL17 UNIPROT IL10 protein P22301 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000782 20154735 NO azuccotti Similarly, an increase in IL-10 expression was observed in mice deficient for the TH1 cell-specific transcription factor T-bet (also known as TBX21) that were infected with M.tuberculosis, suggesting that T-bet might have a role in the negative regulation of IL-10 expression by TH1 cells SIGNOR-254524 SIGNOR-TLymphIL10 T-Lymphocyte: IL10 JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 9606 26260587 YES IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes. SIGNOR-253590 SIGNOR-TLymphIL10 T-Lymphocyte: IL10 IL10RA protein Q13651 UNIPROT JAK1 protein P23458 UNIPROT up-regulates activity 9606 BTO:0000801 26260587 YES IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes. SIGNOR-253589 SIGNOR-TLymphIL10 T-Lymphocyte: IL10 IL10RA protein Q13651 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 26260587 YES lperfetto IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes. SIGNOR-249545 SIGNOR-TLymphIL10 T-Lymphocyte: IL10 STAT3 protein P40763 UNIPROT RORC protein P51449 UNIPROT up-regulates 9606 18454151 NO The inflammatory cytokines IL-6, IL-21 and IL-23 share signaling pathways by activating both STAT1 and STAT3, while IL-1beta is thought to activate the kinases IRAK1 and IRAK2 through recruitment of the adaptor MyD88. Thus, STAT3 is likely to be a common denominator in the induction of RORgammaT and IL-17 expression SIGNOR-254303 SIGNOR-TLymphIL10 T-Lymphocyte: IL10 STAT3 protein P40763 UNIPROT FOXP3 protein Q9BZS1 UNIPROT down-regulates 9606 18156621 NO Our results demonstrate that IL-27 inhibits the acquisition of the Treg phenotype at the level of Foxp3. The inhibitory effect of IL-27 on Treg generation was at least partially signal transducer and activator of transcription 3 (STAT3) dependent as examined by targeted STAT3 protein inhibition using small interfering RNA (siRNA) SIGNOR-254304 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation NfKb-p65/p50 complex SIGNOR-C13 SIGNOR IL4 protein P05112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 15048722 NO We demonstrate that NF-kappa B binds to the IL-4 promoter in vivo upon T cell activation. Inhibition of NF-kappa B nuclear translocation in living cells blocked binding of NF-kappa B to the IL-4 promoter. The data provide first evidence that NF-kappa B is directly involved in IL-4 transcription SIGNOR-254497 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation STAT5A protein P42229 UNIPROT FOXP3 protein Q9BZS1 UNIPROT up-regulates 9606 18270368 YES We demonstrate that the signal transducer and activator of transcription 5 (STAT5)-signaling cytokines, IL-2, IL-15 and to a lesser extent IL-7, induce FOXP3 up-regulation in vitro in activated human Teff cell SIGNOR-254301 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation STAT5A protein P42229 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 10072077 NO Here, we demonstrate that, while lymphoid development is normal, Stat5a/b mutant peripheral T cells are profoundly deficient in proliferation and fail to undergo cell cycle progression or to express genes controlling cell cycle progression SIGNOR-254302 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation NFATC2 protein Q13469 UNIPROT IL4 protein P05112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 11956291 NO IRF4 synergizes with NFATc2 and the IL-4-inducing transcription factor, c-maf, to augment IL-4 promoter activity as well as to elicit significant levels of endogenous IL-4 production SIGNOR-254502 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation LEF1 protein Q9UJU2 UNIPROT IL4 protein P05112 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000782 18579517 NO We identified a high affinity LEF-1-binding site in the negative regulatory element of the IL-4 promoter. Knockdown LEF-1 expression by LEF-1-specific small interfering RNA resulted in an increase in the IL-4 mRNA expression SIGNOR-254504 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation JAK2 protein O60674 UNIPROT STAT6 protein P42226 UNIPROT up-regulates activity phosphorylation 9606 9852261 YES gcesareni Stat6 activation is mediated through jak1 and jak2 tyrosine kinases. SIGNOR-62585 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr637 KFGSLDTyLKKNKNC 9606 BTO:0000007 19364823 YES 16705160:The effect of Ser523 on Jak2 function was independent of Tyr570-mediated inhibition. lperfetto Analysis of in vitro autophosphorylated jak2while cytokine receptor stimulation mediates the phosphorylation of both tyr317 and tyr637, these residues oppositely regulate jak2-dependent signaling: the mutation of tyr317 enhances jak2 function, suggesting a role for the phosphorylation of tyr317 in the inhibition of jak2. Conversely, mutation of tyr637 reduces jak2 signaling, suggesting a role for the phosphorylation of this residue in the activation of jak2. SIGNOR-235885 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1007 VLPQDKEyYKVKEPG -1 9111318 YES Multiple autophosphorylation sites on Jak2, including Y1007 and Y1008. Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop. SIGNOR-251357 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr221 IRAKIQDyHILTRKR 9606 BTO:0000007 15143187 YES JAK2 is autophosphorylated on tyrosines 221 and 1007. tyrosines 221 and 570 in JAK2 may serve as regulatory sites in JAK2, with phosphorylation of tyrosine 221 increasing kinase activity and phosphorylation of tyrosine 570 decreasing kinase activity SIGNOR-251356 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT unknown phosphorylation Tyr1007 VLPQDKEyYKVKEPG -1 9111318 YES Within the Jak2 kinase domain, there is a region that has considerable sequence homology to the regulatory region of the insulin receptor and contains two tyrosines, Y1007 and Y1008, that are potential regulatory sites. Y1007 and Y1008 are sites of trans- or autophosphorylation in vivo and in in vitro kinase reactions. Mutation of Y1007, or both Y1007 and Y1008, to phenylalanine essentially eliminated kinase activity, whereas mutation of Y1008 to phenylalanine had no detectable effect on kinase activity SIGNOR-251358 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity phosphorylation Tyr570 VRREVGDyGQLHETE 9606 BTO:0000007 15143187 YES JAK2 is autophosphorylated on tyrosines 221 and 1007. tyrosines 221 and 570 in JAK2 may serve as regulatory sites in JAK2, with phosphorylation of tyrosine 221 increasing kinase activity and phosphorylation of tyrosine 570 decreasing kinase activity SIGNOR-251359 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr201 DQTPLAIyNSISYKT 9534 BTO:0000298 17027227 YES Site of Jak2 tyrosine autophosphorylation; namely, tyrosine 201. Jak2 tyrosine residue 201 was the principal mediator of SHP-2 binding as conversion of this tyrosine residue to phenylalanine abolished this interaction SIGNOR-251360 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr972 EYLGTKRyIHRDLAT 9606 BTO:0000007 20304997 YES lperfetto Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity SIGNOR-236294 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr813 NSLFTPDyELLTEND 9606 BTO:0000007 15121872 YES 16705160:The effect of Ser523 on Jak2 function was independent of Tyr570-mediated inhibition. lperfetto Tyrosine 813 is a site of jak2 autophosphorylation critical for activation of jak2 by sh2-b betawe show that phosphorylation of tyrosine 813 is required for the sh2 domain-containing adapter protein sh2-b beta to bind jak2 and to enhance the activity of jak2 and stat5b. SIGNOR-235910 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation JAK2 protein O60674 UNIPROT STAT5A protein P42229 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 9575217 YES lperfetto Jak2 kinase induces tyrosine phosphorylation, dimerization, nuclear translocation, and dna binding of a concomitantly expressed stat5 protein SIGNOR-249507 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation POU2F1 protein P14859 UNIPROT IL4 protein P05112 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000782 11781715 NO Here we show that NFAT proteins are unable to bind to a combined octamer/NFAT site unless the octamer proteins are competed away SIGNOR-254505 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation GATA3 protein P23771 UNIPROT IL4 protein P05112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 12876556 NO Initiation of transcription of the gene encoding IL-4 in naive T(H) cells is regulated by the T(H) 2-specific transcription factor GATA3 SIGNOR-254500 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation GATA3 protein P23771 UNIPROT TBX21 protein Q9UL17 UNIPROT down-regulates 9606 16386358 NO Conversely, T-bet is capable of inhibiting GATA-3 (Szabo et al., 2000). The mutual inhibition between GATA-3 and T-bet ensures that Th1 and Th2 cells express one or the other molecule (T-bet in Th1, and GATA-3 in Th2), but not both SIGNOR-254296 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation GATA3 protein P23771 UNIPROT GATA3 protein P23771 UNIPROT up-regulates 9606 16386358 YES Experimental data indeed supports the existence of a positive circuit involvingGATA-3 that excludes IL-4 and STAT-6, specifically in mouse cells SIGNOR-254300 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation IRF4 protein Q15306 UNIPROT IL4 protein P05112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 11956291 NO IRF4 synergizes with NFATc2 and the IL-4-inducing transcription factor, c-maf, to augment IL-4 promoter activity as well as to elicit significant levels of endogenous IL-4 production SIGNOR-254501 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation JUNB protein P17275 UNIPROT IL4 protein P05112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 21799768 NO Our results suggest that the prolonged IL-4 expression in NFAT1 deficient Th2 cells is mediated by preferential binding of JUNB/SATB1 to the IL-4 promoter with permissive chromatin architecture SIGNOR-254503 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation STAT6 protein P42226 UNIPROT GATA3 protein P23771 UNIPROT up-regulates 9606 12947222 YES GATA-3 plays a central role in regulating Th1 and Th2 cell differentiation. Upon interleukin (IL)-4 binding to its receptor, GATA-3 is induced through the action of Stat6 SIGNOR-254299 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation TBX21 protein Q9UL17 UNIPROT IL4 protein P05112 UNIPROT down-regulates transcriptional regulation 9606 BTO:0000782 17541280 NO IL-4 gene transcription is inhibited by T-bet via the suppression of its promoter activity, independently of IFN-gamma. T-bet facilitates Th1 differentiation through not only upregulation of IFN-gamma, but also downregulation of IL-4 gene transcription SIGNOR-254496 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation TBX21 protein Q9UL17 UNIPROT GATA3 protein P23771 UNIPROT down-regulates 9606 16386358 NO Conversely, T-bet is capable of inhibiting GATA-3 (Szabo et al., 2000). The mutual inhibition between GATA-3 and T-bet ensures that Th1 and Th2 cells express one or the other molecule (T-bet in Th1, and GATA-3 in Th2), but not both SIGNOR-254295 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation CIITA protein P33076 UNIPROT IL4 protein P05112 UNIPROT down-regulates transcriptional regulation 9606 BTO:0000782 10946277 NO We identified two domains of CIITA that interact with two distinct domains of CBP/p300 that are also recognized by NF-AT. CIITA mutants that retain the ability to interact with CBP/p300 are sufficient to inhibit NF-AT-mediated IL-4 gene expression SIGNOR-254499 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation NFATC1 protein O95644 UNIPROT IL4 protein P05112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8668213 YES lperfetto Recombinant NFAT1 can mediate transcription of the interleukin-2, interleukin-4, tumor necrosis factor alpha, and granulocyte-macrophage colony-stimulating factor promoters in T cells, suggesting that NFAT1 contributes to the CsA-sensitive transcription of these genes during the immune response. SIGNOR-254498 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation IL4 protein P05112 UNIPROT IL4R protein P24394 UNIPROT up-regulates activity binding 9606 BTO:0000801 18852293 YES lperfetto IL-4 signals through the type I (IL-4Ralpha/common gamma-chain [gammac]) and the type II (IL-4Ralpha/-13Ralpha1) IL-4 receptors, whereas IL-13 utilizes only the type II receptor. SIGNOR-249527 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation IL4 protein P05112 UNIPROT IL4R protein P24394 UNIPROT up-regulates binding -1 10219247 YES gcesareni Nterleukin-4 (il-4) is a principal regulatory cytokine during an immune response and a crucial determinant for allergy and asthma. Il-4 binds with high affinity and specificity to the ectodomain of the il-4 receptor alpha chain (il4-bp). SIGNOR-67217 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation IL4 protein P05112 UNIPROT IL4R protein P24394 UNIPROT up-regulates binding 9606 12704343 YES milica IL-4R Is a 140-kd protein that binds il-4 with high affinity SIGNOR-100762 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation IL4R protein P24394 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 18852293 YES lperfetto Downstream intracellular signaling from the IL-4IL-4Rc complex involves activation of the Jak1 and Jak3 kinases, phosphorylation of the Stat6 transcription factor, and activation of the insulin receptor substrate (IRS)-2 and Dok2-signaling intermediates. IL-13 initially binds to IL-13R1 with intermediate affinity, and then heterodimerizes with IL-4R. The IL-13IL-13R1IL-4R complex activates the Tyk2, Jak2, and Jak1 kinases and Stat6. SIGNOR-249530 SIGNOR-TLymphIL4 T-Lymphocyte: IL4 and its transcriptional regulation IL4R protein P24394 UNIPROT STAT5A protein P42229 UNIPROT up-regulates 9606 20824124 YES Several cytokine receptors share subchains and targets. For example, the common gamma chain (CGC) is shared by IL2, IL4, IL7, IL9 and IL15 receptors that lead to the activation of STAT5 SIGNOR-254298 SIGNOR-TLymphIL6 T-Lymphocyte: IL6 SMAD2/STAT3/EP300 complex SIGNOR-C203 SIGNOR IL17A protein Q16552 UNIPROT up-regulates transcriptional regulation 9606 26194464 YES MARCO ROSINA Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes. SIGNOR-255027 SIGNOR-TLymphIL6 T-Lymphocyte: IL6 SMAD2/STAT3/EP300 complex SIGNOR-C203 SIGNOR RORC protein P51449 UNIPROT up-regulates 9606 26194464 YES MARCO ROSINA Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes. SIGNOR-255026 SIGNOR-TLymphIL6 T-Lymphocyte: IL6 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser255 ELSPTTLsPVNHSLD 9606 26194464 YES MARCO ROSINA Taken together, ERK-mediated Smad2 linker phosphorylation is responsible for TH17 differentiation SIGNOR-255020 SIGNOR-TLymphIL6 T-Lymphocyte: IL6 SMAD2 protein Q15796 UNIPROT SMAD2/STAT3/EP300 complex SIGNOR-C203 SIGNOR form complex binding 9606 26194464 YES MARCO ROSINA Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes. SIGNOR-255023 SIGNOR-TLymphIL6 T-Lymphocyte: IL6 RORC protein P51449 UNIPROT IL17A protein Q16552 UNIPROT up-regulates transcriptional regulation 9606 16990136 YES mrosina We found that RORgt is required for the constitutive expression of IL-17 in intestinal lamina propria T cells and for the in vitro differentiation of Th17 cells from naive CD4+ T cells SIGNOR-255029 SIGNOR-TLymphIL6 T-Lymphocyte: IL6 RORC protein P51449 UNIPROT Th17 phenotype SIGNOR-PH94 SIGNOR up-regulates 9606 16990136 NO MARCO ROSINA Our results demonstrate that RORgt is the transcription factor that directs the differentiation of inflammatory Th17 cells SIGNOR-255028 SIGNOR-TLymphIL6 T-Lymphocyte: IL6 IL6 protein P05231 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity binding 9606 BTO:0001271 15895091 YES miannu A crystal structure of the ligand-binding domains of gp130 in complex with human interleukin-6 (il-6) and its a-receptor (il-6ralpha) revealed a hexameric architecture in which the gp130 membrane-distal regions were approximately 100 a apart, in contrast to the close apposition seen between short cytokine receptor complexes. SIGNOR-48041 SIGNOR-TLymphIL6 T-Lymphocyte: IL6 IL6 protein P05231 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity -1 8511589 NO lperfetto The biological functions of interleukin-6 (IL-6) are mediated through a signal-transducing component of the IL-6 receptor, gp130, which is associated with the ligand-occupied IL-6 receptor (IL-6R) protein. Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130. Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein. Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130. SIGNOR-238617 SIGNOR-TLymphIL6 T-Lymphocyte: IL6 IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 15895091 YES gcesareni We show that the augmentation of the il6 signal by recombinant il6 receptors (ril6r) delivery allows the functional recovery of phagocytes in a peritonitis mouse model. SIGNOR-137236 SIGNOR-TLymphIL6 T-Lymphocyte: IL6 IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 23663276 YES milica In classical il-6 signaling, the cytokine first binds to the membrane-bound il-6 receptor (il-6r;cd126) that is induced to associate with a homodimer of gp130 which then transmits the intracellular signal. SIGNOR-202030 SIGNOR-TLymphIL6 T-Lymphocyte: IL6 IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 8676083 YES fspada We first observed that cultured mouse embryonic dorsal root ganglia exhibited dramatic neurite extension by simultaneous addition of il-6 and soluble il-6r (sil-6r), a complex that is known to interact with and activate a signal transducing receptor component, gp130 SIGNOR-42866 SIGNOR-TLymphIL6 T-Lymphocyte: IL6 EP300 protein Q09472 UNIPROT SMAD2/STAT3/EP300 complex SIGNOR-C203 SIGNOR form complex binding 9606 26194464 YES MARCO ROSINA Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes. SIGNOR-255025 SIGNOR-TLymphIL6 T-Lymphocyte: IL6 JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity binding 9606 24710148 YES lperfetto The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3). SIGNOR-236369 SIGNOR-TLymphIL6 T-Lymphocyte: IL6 JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 19723038 YES lperfetto The activation of stat-3 is regulated by phosphorylation of tyrosine 705 by receptor and nonreceptor protein tyrosine kinases. These include epidermal growth factor receptor (egfr) kinase, src, janus-activated kinases (jak), and extracellular signal-regulated kinase (erk). SIGNOR-187775 SIGNOR-TLymphIL6 T-Lymphocyte: IL6 JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 9606 26260587 YES IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes. SIGNOR-253590 SIGNOR-TLymphIL6 T-Lymphocyte: IL6 STAT3 protein P40763 UNIPROT RORC protein P51449 UNIPROT up-regulates 9606 18454151 NO The inflammatory cytokines IL-6, IL-21 and IL-23 share signaling pathways by activating both STAT1 and STAT3, while IL-1beta is thought to activate the kinases IRAK1 and IRAK2 through recruitment of the adaptor MyD88. Thus, STAT3 is likely to be a common denominator in the induction of RORgammaT and IL-17 expression SIGNOR-254303 SIGNOR-TLymphIL6 T-Lymphocyte: IL6 STAT3 protein P40763 UNIPROT FOXP3 protein Q9BZS1 UNIPROT down-regulates 9606 18156621 NO Our results demonstrate that IL-27 inhibits the acquisition of the Treg phenotype at the level of Foxp3. The inhibitory effect of IL-27 on Treg generation was at least partially signal transducer and activator of transcription 3 (STAT3) dependent as examined by targeted STAT3 protein inhibition using small interfering RNA (siRNA) SIGNOR-254304 SIGNOR-TLymphIL6 T-Lymphocyte: IL6 STAT3 protein P40763 UNIPROT SMAD2/STAT3/EP300 complex SIGNOR-C203 SIGNOR form complex binding 9606 26194464 YES MARCO ROSINA Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes. SIGNOR-255024 SIGNOR-TLymphIL6 T-Lymphocyte: IL6 IL6R protein P08887 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 BTO:0000785 11238858 YES gcesareni Part of the receptor for interleukin 6. Binds to il6 with low affinity, but does not transduce a signal. Signal activation necessitate an association with il6st. Activation may lead to the regulation of the immune response, acute-phase reactions and hematopoiesis. SIGNOR-105504 SIGNOR-TLymphIL6 T-Lymphocyte: IL6 IL6R protein P08887 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 23663276 YES milica In classical il-6 signaling, the cytokine first binds to the membrane-bound il-6 receptor (il-6r;cd126) that is induced to associate with a homodimer of gp130 which then transmits the intracellular signal. SIGNOR-202033 SIGNOR-TLymphIL6 T-Lymphocyte: IL6 IL6ST protein P40189 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity phosphorylation Ser659 WPNVPDPsKSHIAQW -1 8511589 YES lperfetto The biological functions of interleukin-6 (IL-6) are mediated through a signal-transducing component of the IL-6 receptor, gp130, which is associated with the ligand-occupied IL-6 receptor (IL-6R) protein. Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130. Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein. Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130. SIGNOR-238621 SIGNOR-TLymphIL6 T-Lymphocyte: IL6 IL6ST protein P40189 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity phosphorylation Ser661 NVPDPSKsHIAQWSP -1 8511589 YES lperfetto The biological functions of interleukin-6 (IL-6) are mediated through a signal-transducing component of the IL-6 receptor, gp130, which is associated with the ligand-occupied IL-6 receptor (IL-6R) protein. Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130. Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein. Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130. SIGNOR-238625 SIGNOR-TLymphIL6 T-Lymphocyte: IL6 IL6ST protein P40189 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 24710148 YES milica The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3). SIGNOR-204841 SIGNOR-TLymphIL6 T-Lymphocyte: IL6 IL6ST protein P40189 UNIPROT JAK1 protein P23458 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 23663276 YES milica Il-6 family members typically signal through the common gp130 receptor, with the janus kinase/signal transducer and activator of transcription (jak/stat) pathway being the major intracellular mediator of their effects. SIGNOR-202036 SIGNOR-TLymphIL6 T-Lymphocyte: IL6 IL6ST protein P40189 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 16306329 NO mrosina Upon formation of the IL-6/IL-6Ralpha/gp130 hexameric signaling complex, two distinct signaling pathways are activated: 1) Janus kinase (JAK)/signal transducers and activator of transcription (STAT) and 2) the Src homology 2-containing tyrosine phosphatase (SHP-2)/extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathways SIGNOR-255022 SIGNOR-TLymphTGFB T-Lymphocyte: TGF beta SMAD2/STAT3/EP300 complex SIGNOR-C203 SIGNOR IL17A protein Q16552 UNIPROT up-regulates transcriptional regulation 9606 26194464 YES MARCO ROSINA Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes. SIGNOR-255027 SIGNOR-TLymphTGFB T-Lymphocyte: TGF beta SMAD2/STAT3/EP300 complex SIGNOR-C203 SIGNOR RORC protein P51449 UNIPROT up-regulates 9606 26194464 YES MARCO ROSINA Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes. SIGNOR-255026 SIGNOR-TLymphTGFB T-Lymphocyte: TGF beta SMAD3/PIAS3 complex SIGNOR-C204 SIGNOR STAT3 protein P40763 UNIPROT down-regulates 9606 26194464 YES mrosina In summary, the TGF-b/IL-6/TCR-pERK-Smad2L (Ser255) axis is the positive regulator, whereas unphosphorylated Smad3C-PIAS3 complex is the negative regulator of STAT3-induced transcriptional processes for TH17 differentiation SIGNOR-255036 SIGNOR-TLymphTGFB T-Lymphocyte: TGF beta ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser255 ELSPTTLsPVNHSLD 9606 26194464 YES MARCO ROSINA Taken together, ERK-mediated Smad2 linker phosphorylation is responsible for TH17 differentiation SIGNOR-255020 SIGNOR-TLymphTGFB T-Lymphocyte: TGF beta TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity binding 9606 22326956 YES lperfetto TGF-beta signaling mediates a wide range of biological activities in development and disease. TGF-beta ligands signal through heterodimeric type I and type II receptors (TGF-beta receptor type I [TbetaRI, also known as ALK5 and TGFBR1] and TbetaRII) that are members of the serine/threonine kinase family. SIGNOR-196022 SIGNOR-TLymphTGFB T-Lymphocyte: TGF beta TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates binding 9606 26194464 YES MARCO ROSINA TGF-b ligands bind to TGF-b type II receptor (TbRII), which transphosphorylates and activates TGF-b type I receptor (TbRI). SIGNOR-255031 SIGNOR-TLymphTGFB T-Lymphocyte: TGF beta TGFB1 protein P01137 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 26194464 YES MARCO ROSINA TGF-b ligands bind to TGF-b type II receptor (TbRII), which transphosphorylates and activates TGF-b type I receptor (TbRI). SIGNOR-255030 SIGNOR-TLymphTGFB T-Lymphocyte: TGF beta STAT5A protein P42229 UNIPROT FOXP3 protein Q9BZS1 UNIPROT up-regulates 9606 18270368 YES We demonstrate that the signal transducer and activator of transcription 5 (STAT5)-signaling cytokines, IL-2, IL-15 and to a lesser extent IL-7, induce FOXP3 up-regulation in vitro in activated human Teff cell SIGNOR-254365 SIGNOR-TLymphTGFB T-Lymphocyte: TGF beta TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates phosphorylation 9606 26194464 YES MARCO ROSINA TGF-b ligands bind to TGF-b type II receptor (TbRII), which transphosphorylates and activates TGF-b type I receptor (TbRI). SIGNOR-255032 SIGNOR-TLymphTGFB T-Lymphocyte: TGF beta SMAD2 protein Q15796 UNIPROT SMAD2/STAT3/EP300 complex SIGNOR-C203 SIGNOR form complex binding 9606 26194464 YES MARCO ROSINA Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes. SIGNOR-255023 SIGNOR-TLymphTGFB T-Lymphocyte: TGF beta SMAD3 protein P84022 UNIPROT FOXP3 protein Q9BZS1 UNIPROT up-regulates 9606 19701891 YES TGF-beta1-activated Smad3 plays a major role in the expression of Foxp3, since TGF-beta1-induced-Treg generation from Smad3(-/-) mice is markedly reduced and abolished by inactivating Smad2 SIGNOR-254362 SIGNOR-TLymphTGFB T-Lymphocyte: TGF beta SMAD3 protein P84022 UNIPROT FOXP3 protein Q9BZS1 UNIPROT up-regulates 9606 15367216 YES The TCR, IL-2R, and TbetaR must all be stimulated to induce Foxp3 + Tregs. Failure to engage any one of these receptors prevents the generation of Foxp3 + Tregs SIGNOR-254363 SIGNOR-TLymphTGFB T-Lymphocyte: TGF beta SMAD3 protein P84022 UNIPROT SMAD3/PIAS3 complex SIGNOR-C204 SIGNOR form complex binding 9606 26194464 YES mrosina In summary, the TGF-b/IL-6/TCR-pERK-Smad2L (Ser255) axis is the positive regulator, whereas unphosphorylated Smad3C-PIAS3 complex is the negative regulator of STAT3-induced transcriptional processes for TH17 differentiation SIGNOR-255034 SIGNOR-TLymphTGFB T-Lymphocyte: TGF beta FOXP3 protein Q9BZS1 UNIPROT T-reg_differentiation phenotype SIGNOR-PH91 SIGNOR up-regulates 9606 15785758 NO mrosina Viewed as a whole, the available data demonstrate essential involvement of Foxp3 in the development and function of CD4 + CD25 + T reg cells. SIGNOR-254970 SIGNOR-TLymphTGFB T-Lymphocyte: TGF beta RORC protein P51449 UNIPROT IL17A protein Q16552 UNIPROT up-regulates transcriptional regulation 9606 16990136 YES mrosina We found that RORgt is required for the constitutive expression of IL-17 in intestinal lamina propria T cells and for the in vitro differentiation of Th17 cells from naive CD4+ T cells SIGNOR-255029 SIGNOR-TLymphTGFB T-Lymphocyte: TGF beta RORC protein P51449 UNIPROT Th17 phenotype SIGNOR-PH94 SIGNOR up-regulates 9606 16990136 NO MARCO ROSINA Our results demonstrate that RORgt is the transcription factor that directs the differentiation of inflammatory Th17 cells SIGNOR-255028 SIGNOR-TLymphTGFB T-Lymphocyte: TGF beta PIAS3 protein Q9Y6X2 UNIPROT SMAD3/PIAS3 complex SIGNOR-C204 SIGNOR form complex binding 9606 26194464 YES mrosina In summary, the TGF-b/IL-6/TCR-ERK-Smad2L (Ser255) axis is the positive regulator, whereas unphosphorylated Smad3C-PIAS3 complex is the negative regulator of STAT3-induced transcriptional processes for TH17 differentiation SIGNOR-255035 SIGNOR-TLymphTGFB T-Lymphocyte: TGF beta EP300 protein Q09472 UNIPROT SMAD2/STAT3/EP300 complex SIGNOR-C203 SIGNOR form complex binding 9606 26194464 YES MARCO ROSINA Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes. SIGNOR-255025 SIGNOR-TLymphTGFB T-Lymphocyte: TGF beta TGFBR1 protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation 9606 19701891 YES miannu The binding of TGF‐β1 to its receptor complex activates the intracellular kinase domain of TGF‐βRII, which leads to the phosphorylation and activation of Smad2, Smad3 and Smad4 as well as non‐Smad proteins (Smad‐independent pathway) SIGNOR-254361 SIGNOR-TLymphTGFB T-Lymphocyte: TGF beta TGFBR1 protein P36897 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 26194464 NO MARCO ROSINA TbRI phosphorylates not only the C-termini of R-Smads but also activates various protein kinases including mitogen-activated protein kinases (MAPKs): extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK (p38), which then phosphorylate the variable linker regions of R-Smad SIGNOR-255033 SIGNOR-TLymphTGFB T-Lymphocyte: TGF beta STAT3 protein P40763 UNIPROT FOXP3 protein Q9BZS1 UNIPROT down-regulates 9606 18156621 NO Our results demonstrate that IL-27 inhibits the acquisition of the Treg phenotype at the level of Foxp3. The inhibitory effect of IL-27 on Treg generation was at least partially signal transducer and activator of transcription 3 (STAT3) dependent as examined by targeted STAT3 protein inhibition using small interfering RNA (siRNA) SIGNOR-254364 SIGNOR-TLymphTGFB T-Lymphocyte: TGF beta STAT3 protein P40763 UNIPROT SMAD2/STAT3/EP300 complex SIGNOR-C203 SIGNOR form complex binding 9606 26194464 YES MARCO ROSINA Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes. SIGNOR-255024 SIGNOR-TLymphTGFB T-Lymphocyte: TGF beta JUN protein P05412 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 23936544 YES lperfetto MAPKs have cis-acting regulatory elements in the mouse-TGF promoter region, which respond to various transcription factors, including specificity protein-1 and activating protein 1. Thus, it is possible that apoptotic cell-induced TGF-beta mRNA expression is mediated through activation of these transcription factors via MAPK signaling. Xiao et al. reported that all of the MAPK members, including p38/ERK/JNK, are required for apoptotic Jurkat cells up-regulation of TGF-beta production SIGNOR-251713 SIGNOR-Tnfa_Notch_crosstalk Tnfa_Notch_crosstalk RBPJ/NOTCH complex SIGNOR-C97 SIGNOR HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7566092 YES lperfetto Here we show that activated forms of mNotch associate with the human analogue of Su(H), KBF2/RBP-J kappa (refs 8,9) and act as transcriptional activators through the KBF2-binding sites of the HES-1 promoter. SIGNOR-209590 SIGNOR-Tnfa_Notch_crosstalk Tnfa_Notch_crosstalk gamma-secretase complex SIGNOR-C98 SIGNOR NOTCH1 protein P46531 UNIPROT up-regulates activity cleavage 9606 25610395 YES lperfetto The membrane-bound Notch segment that results from this cleavage, known as Notch Intracellular Truncation domain (NEXT), is a γ-secretase substrate. γ-Secretase performs the subsequent cleavage at S3, releasing Notch intracellular domain (NICD) from the membrane and allowing for signal transduction through binding with the CBL-1, Su(H), Lag-1 family of DNA binding proteins. SIGNOR-209717 SIGNOR-Tnfa_Notch_crosstalk Tnfa_Notch_crosstalk IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 BTO:0000567 9346241 YES lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-209773 SIGNOR-Tnfa_Notch_crosstalk Tnfa_Notch_crosstalk IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 9346241 YES lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-216385 SIGNOR-Tnfa_Notch_crosstalk Tnfa_Notch_crosstalk IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 9346241 YES lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-216389 SIGNOR-Tnfa_Notch_crosstalk Tnfa_Notch_crosstalk IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation 9606 21232017 YES lperfetto Tak1 become activated and then phosphorilates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation SIGNOR-216396 SIGNOR-Tnfa_Notch_crosstalk Tnfa_Notch_crosstalk TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT up-regulates activity binding 9606 11502070 YES lperfetto Binding of tnf to the extracellular domain of tnfrsf1a leads to homotrimerization. SIGNOR-109716 SIGNOR-Tnfa_Notch_crosstalk Tnfa_Notch_crosstalk TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT up-regulates activity binding 9606 23070005 YES miannu For TNFR1, the cytokine TNFα binds to the receptor and triggers its trimerization, which leads to the assembly of the receptor complex and initiation of signaling. SIGNOR-199091 SIGNOR-Tnfa_Notch_crosstalk Tnfa_Notch_crosstalk TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT up-regulates activity binding 9606 10634209 YES lperfetto TNF-induced apoptosis is mediated primarily through the activation of type I receptors SIGNOR-226676 SIGNOR-Tnfa_Notch_crosstalk Tnfa_Notch_crosstalk TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination Lys377 NEPSLQSkLQDEANY 9606 18621737 YES lperfetto Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2. SIGNOR-179456 SIGNOR-Tnfa_Notch_crosstalk Tnfa_Notch_crosstalk TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination Lys377 NEPSLQSkLQDEANY 10090 BTO:0002572;BTO:0000801 21232017 YES lperfetto Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2. SIGNOR-235407 SIGNOR-Tnfa_Notch_crosstalk Tnfa_Notch_crosstalk TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 10090 BTO:0002572;BTO:0000801 21232017 YES gcesareni Rip1 is known to directly interact with traf2 SIGNOR-245032 SIGNOR-Tnfa_Notch_crosstalk Tnfa_Notch_crosstalk TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination Lys377 NEPSLQSkLQDEANY 9606 BTO:0000007 8702708 YES lperfetto Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2. SIGNOR-42984 SIGNOR-Tnfa_Notch_crosstalk Tnfa_Notch_crosstalk TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination Lys377 NEPSLQSkLQDEANY 9606 9712898 YES lperfetto Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2. SIGNOR-59689 SIGNOR-Tnfa_Notch_crosstalk Tnfa_Notch_crosstalk DLL1 protein O00548 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 9606 BTO:0000776 16140393 YES lperfetto Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate. SIGNOR-209732 SIGNOR-Tnfa_Notch_crosstalk Tnfa_Notch_crosstalk RIPK1 protein Q13546 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates activity binding 10090 BTO:0000452 10795740 YES gcesareni We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation SIGNOR-245026 SIGNOR-Tnfa_Notch_crosstalk Tnfa_Notch_crosstalk HES1 protein Q14469 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR down-regulates activity binding 10090 BTO:0000562 16682003 YES lperfetto Here we show that hrt2 and hes1 interact with rbp-jkappa to negatively regulate notch-dependent activation of hrt and hes expression. SIGNOR-209756 SIGNOR-Tnfa_Notch_crosstalk Tnfa_Notch_crosstalk TRADD protein Q15628 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 8612133 YES lperfetto We show that tradd interacts strongly with rip;rip is a serinethreonine kinase that is recruited by tradd to tnfr1 in a tnf-dependent process. SIGNOR-40043 SIGNOR-Tnfa_Notch_crosstalk Tnfa_Notch_crosstalk TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 10090 14585074 YES lperfetto Tradd mediates recruitment of the traf2 adaptor protein SIGNOR-118770 SIGNOR-Tnfa_Notch_crosstalk Tnfa_Notch_crosstalk TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 10090 BTO:0000459 18621737 YES lperfetto The high affinity of the tradd-traf2 interaction is required for efficient suppression of apoptosis upon stimulation of the tumor necrosis factor receptor1 (tnfr1), tnf-receptor-associated death domain (tradd) provides a scaffold for the assembly of complex i at the plasma membrane by binding receptor interacting protein 1 (rip1), tnfreceptor- associated factor 2 ,traf2 these results provide evidence that tradd can serve as an adaptor protein and recruit traf1, traf2, or both to tnfrsf1a. The demonstration that tradd interacts with traf2 and fadd, and can recruit both to tnfrsf1a, suggested that traf2 and fadd may be involved in tnfrsf1a tradd-mediated signaling. That these interactions define two distinct signaling pathways emanating from tradd (figure 9) is supported by the ability of traf2 and fadd to activate nf-kb and induce apoptosis, respectively. SIGNOR-179446 SIGNOR-Tnfa_Notch_crosstalk Tnfa_Notch_crosstalk TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 9606 BTO:0000007 27383048 YES miannu Upon stimulation with TNFα, TNFR1 recruits TRADD, which provides a scaffold for the assembly of complex I at the plasma membrane by binding with RIP1, TRAF2 and cIAP. SIGNOR-42980 SIGNOR-Tnfa_Notch_crosstalk Tnfa_Notch_crosstalk TNFRSF1A protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 11502070 YES lperfetto The death domain of tnfrsf1a provides a novel molecular interface that interacts specifically with the death domain of tradd. SIGNOR-109719 SIGNOR-Tnfa_Notch_crosstalk Tnfa_Notch_crosstalk TNFRSF1A protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 BTO:0000007 7758105 YES lperfetto We have identified a novel 34 kda protein, designated tradd, that specifically interacts with an intracellular domain of tnfr1 tradd interacts with the death domain of tnfrsf1a to initiate distinct signaling cascades for two of the most important biological activities of tnf, nf-kb activation and programmed cell death tradd, a novel protein that specifically interacts with the death domain of tnfr1 and activates signaling pathways for both of these activities when overexpressed. SIGNOR-32739 SIGNOR-Tnfa_Notch_crosstalk Tnfa_Notch_crosstalk NFKBIA protein P25963 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 1340770 YES lperfetto Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b SIGNOR-217394 SIGNOR-Tnfa_Notch_crosstalk Tnfa_Notch_crosstalk NFKBIA protein P25963 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 9914500 YES lperfetto In nonstimulated cells, nf-kappab is present in the cytosol where it is complexed to its inhibitor ikappab however, we found that only one of the activities, namely the ikk1/2 complex, exists as a pre-assembled kinase-substrate complex in which the ikks are directly or indirectly associated with several nf-kappab-related and ikappab-related proteins: rela, relb, crel, p100, p105, ikappa balpha, ikappa bbeta and ikappa bepsilon. SIGNOR-64092